NOD1, NOD2, CIITA, and NLRP10 that are signaling receptors and are associated to adaptive immunity. NLRC4 and NLRP3 are linked to the formation of the inflammasome and finally NLRP1, NLRP6, NLRP12, and NLRC5 participate both in signaling as well as in the formation of the inflammasome [75]. In relation to the formation of the inflammasome, NLRP 1, 2, 3, 6, 7, 12, NLRC4/N, and AIP 2, 5 have been found to participate when those receptors sense PAMPs or DAMPs (damage-associated molecular patterns). Also, it has been documented that CIITA and NLRC5 can be activated by cytokines that lead to the transcription of MHC I and II, and NOD1-2 have TLR-like activity with the recognition of PAMPs and triggering of inflammatory signaling cascades. Other members such as NLRP 2, 4, 6, 11, 12, NLRX1, NLRC3, etc. participate in the inhibition of the NF-κB pathways [76, 77]. Finally, NLRP 10 and 12 participate in cellular migration. In particular, NLRP10 plays a critical role in antigen-primed DC migration in draining lymph nodes [78], and NLRP-12 regulates migration of DC to a CCR7

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 53

chemokine gradient, thus resulting in a reduced T cell response to antigen [79].

**2.4. C-type lectin receptors (CLRs)**

CD8α+

In conclusion, this large family of intracellular receptors can recognize viral, bacterial, protozoan, and fungal antigens that trigger cellular innate and adaptive immune responses.

Myeloid cells, including DC and macrophages, express a large number of C-type lectin receptors that are one of the most important PRRs that recognize carbohydrates [80]. They can have a transmembrane or soluble localization and can trigger phagocytic and inflammatory responses through the recognition of PAMPs, DAMPs, and tumor-associated molecular patterns (TAMPs) [81]. The common structure in these receptors is the carbohydrate recognition domain (CRD), which can be found in different numbers and arrangements. They also present an ITAM (immunoreceptor tyrosine-based activation) like motif or an ITIM (immunoreceptor tyrosine-based inhibition) motif [82]. A wide array of carbohydrates are recognized by CLRs, among those that can be found are high mannose glycans, mannose, mannosyl fatty acids, fucose glycans, Lewis antigens, glucans, among others. The recognition of the ligand by a CLR can activate or inhibit responses dependent or independent of the Syk signaling pathway [83]. This family of receptors has been classified according to their structure in 17 groups that comprise almost 50 proteins. The groups that comprise the soluble receptors are: I (proteoglycans), III (collectins), VII (free CTLD), IX (tetranectin), and XII (CTLD/acidic neck). On the other hand, transmembrane receptors are grouped as follows: II (type 2 receptors), IV (selectins), V (NK cell receptors), VI (MMR), X (polycystin), XI (attractin), and XIV (endosialin) [82]. Several CLRs are present in DC and the best characterized are DCIR, DCSIGN (CD209), Dectin1, Langerin, and MMR (CD206). Langerin (CD207) on LC in the epithelial layer of the skin has unique carbohydrate specificity for high mannose and LeY carbohydrates and is involved in the recognition of various viruses [84]. DEC 205 has extensively been employed for target delivery of antigens to DC in murine and human studies [16]. It has been shown that targeting antigen to the DEC205 receptor improves humoral and cellular immune responses when DC are stimulated with activating agents or adjuvants such as poly I:C [85]. In mice, this receptor is expressed on cortical thymic epithelium, thymic medullary DC (CD11c+

), and subsets of peripheral DC (splenic, lymph node DC, dermal, interstitial DC, and Langerhans cells) [86]. In contrast, DC-SIGN (CD209) is merely expressed on moDCs and

,

#### **2.2. RIG-I-like receptors (RLRs)**

Retinoic acid-inducible gene-I-like receptors (RLRs) are intracellular receptors and, to this date, are a family of three members, which are RIG-I, melanoma-differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). The ligand for RIG-I is RNA (5′ -PPP single-stranded RNA and short double-stranded RNA), MDA5 recognizes RNA (poly IC and long double-stranded RNA) and LGP2 recognizes RNA [72]. All three receptors are composed of a central DExD/H box helicase domain, which coordinates RNA binding and a C-terminal regulatory domain that is implicated in RNA binding. In addition, RIG-I and MDA5 contain two CARD domains (caspase activation and recruitment) that have critical signal activity and are involved in the innate immune and inflammatory responses upon RNA detection [73]. The activation of these receptors induces the production of type I IFN characterized by its antiviral and antibacterial activity; thus, RLRs are an important complement of the immune response, particularly, with intracellular pathogens, and could be important in the response against antigenic RNA from intracellular protozoa. It has been showed that RLRs responses are independent of TLRs responses [74].

#### **2.3. NOD-like receptors (NLRs)**

One important family of receptors found in DC is the nucleotide-binding oligomerization domain-containing receptors (NLRs), which are a family of 22 protein members in humans that can be classified into five subfamilies according to their structure: NLRA (CIITA), NLRB (NAIPs), NLRC (NOD1, NOD2 and NLRC3-5), NLRP (NLRP 1-14), and NLRX [74]. Their basic structure consists of a central nucleotide-binding domain (NBD), a carboxy-terminal leucine-rich repeats (LRR), and an amino-terminal effector domain. Some of the ligands that bind to these receptors are iE-DAP, MDP, RNA, ATP, bacterial toxins, uric acid, CPPD, amyloid-b, and anthrax lethal toxin [68]. NLRs are linked to different functions, as is the case of NOD1, NOD2, CIITA, and NLRP10 that are signaling receptors and are associated to adaptive immunity. NLRC4 and NLRP3 are linked to the formation of the inflammasome and finally NLRP1, NLRP6, NLRP12, and NLRC5 participate both in signaling as well as in the formation of the inflammasome [75]. In relation to the formation of the inflammasome, NLRP 1, 2, 3, 6, 7, 12, NLRC4/N, and AIP 2, 5 have been found to participate when those receptors sense PAMPs or DAMPs (damage-associated molecular patterns). Also, it has been documented that CIITA and NLRC5 can be activated by cytokines that lead to the transcription of MHC I and II, and NOD1-2 have TLR-like activity with the recognition of PAMPs and triggering of inflammatory signaling cascades. Other members such as NLRP 2, 4, 6, 11, 12, NLRX1, NLRC3, etc. participate in the inhibition of the NF-κB pathways [76, 77]. Finally, NLRP 10 and 12 participate in cellular migration. In particular, NLRP10 plays a critical role in antigen-primed DC migration in draining lymph nodes [78], and NLRP-12 regulates migration of DC to a CCR7 chemokine gradient, thus resulting in a reduced T cell response to antigen [79].

In conclusion, this large family of intracellular receptors can recognize viral, bacterial, protozoan, and fungal antigens that trigger cellular innate and adaptive immune responses.

#### **2.4. C-type lectin receptors (CLRs)**

form recognizes different ligands and induces the production of various cytokines and chemokines [65–67]. TLR1 and TLR2 recognize triacyl lipopeptides, TLR2 and TLR6 sense diacyl lipopeptides, lipoteichoic acid, and zymosan. Also, TLR2 recognizes peptidoglycans, lipoarabinomannan, porins, glycosylphosphatidylinositol-anchored mucin-like, and hemagglutinin. TLR3 recognizes double-stranded RNA, TLR4 senses LPS and envelope proteins. TLR5 recognizes flagellin, TLR7 and 8 can recognize single-stranded RNA and finally TLR9 recognizes DNA CpG and malaria hemozoin [68]. DCs show different expression levels of TLRs and respond dissimilarly to TLR ligands. The expression of TLRs varies with species, DC subtype, and maturation stage. All human TLRs are present in immune cells, specifically in DC, TLR1, 2, 3, 4, 7 and 9 have been shown to be present [69]. TLR10 is not present in human dendritic cells; nevertheless, it has been recently demonstrated that this receptor could be found intracellularly in endosomes and can recognize dsRNA [70]. When TLRs bind their ligands (PAMPs), this (among another variables) can trigger changes in the maturation, migration, and actions of DC. This phenomenon initiates an inflammatory response characterized by the production of cytokines, cellular migration, and directly or indirectly the activation and generation of Th1, Th2, Th17, Treg, and even

Retinoic acid-inducible gene-I-like receptors (RLRs) are intracellular receptors and, to this date, are a family of three members, which are RIG-I, melanoma-differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). The ligand for RIG-I is RNA (5′ -PPP single-stranded RNA and short double-stranded RNA), MDA5 recognizes RNA (poly IC and long double-stranded RNA) and LGP2 recognizes RNA [72]. All three receptors are composed of a central DExD/H box helicase domain, which coordinates RNA binding and a C-terminal regulatory domain that is implicated in RNA binding. In addition, RIG-I and MDA5 contain two CARD domains (caspase activation and recruitment) that have critical signal activity and are involved in the innate immune and inflammatory responses upon RNA detection [73]. The activation of these receptors induces the production of type I IFN characterized by its antiviral and antibacterial activity; thus, RLRs are an important complement of the immune response, particularly, with intracellular pathogens, and could be important in the response against antigenic RNA from intracellular protozoa. It has been

One important family of receptors found in DC is the nucleotide-binding oligomerization domain-containing receptors (NLRs), which are a family of 22 protein members in humans that can be classified into five subfamilies according to their structure: NLRA (CIITA), NLRB (NAIPs), NLRC (NOD1, NOD2 and NLRC3-5), NLRP (NLRP 1-14), and NLRX [74]. Their basic structure consists of a central nucleotide-binding domain (NBD), a carboxy-terminal leucine-rich repeats (LRR), and an amino-terminal effector domain. Some of the ligands that bind to these receptors are iE-DAP, MDP, RNA, ATP, bacterial toxins, uric acid, CPPD, amyloid-b, and anthrax lethal toxin [68]. NLRs are linked to different functions, as is the case of

showed that RLRs responses are independent of TLRs responses [74].

B lymphocyte responses [71].

52 Dendritic Cells

**2.2. RIG-I-like receptors (RLRs)**

**2.3. NOD-like receptors (NLRs)**

Myeloid cells, including DC and macrophages, express a large number of C-type lectin receptors that are one of the most important PRRs that recognize carbohydrates [80]. They can have a transmembrane or soluble localization and can trigger phagocytic and inflammatory responses through the recognition of PAMPs, DAMPs, and tumor-associated molecular patterns (TAMPs) [81]. The common structure in these receptors is the carbohydrate recognition domain (CRD), which can be found in different numbers and arrangements. They also present an ITAM (immunoreceptor tyrosine-based activation) like motif or an ITIM (immunoreceptor tyrosine-based inhibition) motif [82]. A wide array of carbohydrates are recognized by CLRs, among those that can be found are high mannose glycans, mannose, mannosyl fatty acids, fucose glycans, Lewis antigens, glucans, among others. The recognition of the ligand by a CLR can activate or inhibit responses dependent or independent of the Syk signaling pathway [83]. This family of receptors has been classified according to their structure in 17 groups that comprise almost 50 proteins. The groups that comprise the soluble receptors are: I (proteoglycans), III (collectins), VII (free CTLD), IX (tetranectin), and XII (CTLD/acidic neck). On the other hand, transmembrane receptors are grouped as follows: II (type 2 receptors), IV (selectins), V (NK cell receptors), VI (MMR), X (polycystin), XI (attractin), and XIV (endosialin) [82]. Several CLRs are present in DC and the best characterized are DCIR, DCSIGN (CD209), Dectin1, Langerin, and MMR (CD206). Langerin (CD207) on LC in the epithelial layer of the skin has unique carbohydrate specificity for high mannose and LeY carbohydrates and is involved in the recognition of various viruses [84]. DEC 205 has extensively been employed for target delivery of antigens to DC in murine and human studies [16]. It has been shown that targeting antigen to the DEC205 receptor improves humoral and cellular immune responses when DC are stimulated with activating agents or adjuvants such as poly I:C [85]. In mice, this receptor is expressed on cortical thymic epithelium, thymic medullary DC (CD11c+ , CD8α+ ), and subsets of peripheral DC (splenic, lymph node DC, dermal, interstitial DC, and Langerhans cells) [86]. In contrast, DC-SIGN (CD209) is merely expressed on moDCs and on CD14+ dDCs in dermal layers of the skin and has specificity for mannose and all Lewis type carbohydrates (Lewis A, B, X, and Y) [87]. This receptor is often endosialin with the MR (CD206) and shares mannose specificity [88]. DCIR (for DC immunoreceptor) (CLEC4a) has broad carbohydrate specificity for mannose and fucose [89, 90] and has been shown to participate in T cell responses. Different from other CLRs, DCIR contains an ITIM motif and, upon triggering with Abs, inhibits the production of inflammatory cytokines and, thus, has been associated with homeostatic control and control of inflammation [91–93]. Also, it has been shown that DCIR can participate in the capture of HIV-1 and promote infection in trans and in cis of autologous CD4+ T cells from human immature monocyte-derived DCs [94].

**3.1. Interaction of dendritic cells with** *Leishmania*

*Leishmania* is an obligate intracellular parasite that presents two morphological stages: the flagellated promastigote that is found in the salivary glands of the insect vector and the aflagellated amastigote that is the intracellular form found in the vertebrate host. This genus of parasites is constituted by diverse species that are morphologically indistinguishable and are grouped in three subgenera: *Leishmania*, *Viannia*, and *Sauroleishmania*. The species that cause infection in humans and other mammals are found in the subgenus *Leishmania* and *Viannia*. *Sauroleishmania* has been only found to infect some reptiles. Species belonging to *Leishmania* are characterized for having a suprapyloric development and among these are: *donovani, chagasi (infantum), major, tropica, aethiopica, mexicana (pifanoi), amazonensis,* and *venezuelensis.* On the other hand, the species of the subgenus *Viannia* have a peripyloric development and are *braziliensis, guayanensis, peruviana,* and *panamensis. Leishmania* is transmitted by Diptera belonging to the family Psychodidae, specifically, by females of the genus *Lutzomyia* and *Phlebotomus* [99, 100]*. Lutzomyia* is the transmitter of leishmaniasis in America, and

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 55

*Leishmania* life cycle starts when the insect vector feeds blood from the vertebrate host and inoculates promastigotes in the superior dermis [103]. Then, promastigotes are recognized through different receptors such as CR3 [104], C-type lectin receptors, and FcγR and are phagocytosed by dermal macrophages, where they transform to amastigotes [105] and also infect neutrophils. Thanks to a series of events such as the inhibition of phagocytosis, resistance to microbicidal mechanisms, and inhibition of host cells apoptosis, amastigotes manage to survive inside macrophages and duplicate until they lyse them and infect new surrounding cells, such as dendritic cells. If the parasite is not able to inhibit the different microbicidal mechanisms of macrophages, they will be able to destroy them mainly through the production of nitric oxide and induce the activation and recruitment of proinflammatory cells such as cutaneous mast cells, neutrophils, and inflammatory monocytes that lead to the development of a focus of chronic inflammation in the site of infection, which will be evident in the patient [105, 106]. The female sand fly when ingests blood from an infected host draws infected cells

One of the most studied interactions of DC with a parasite is the interaction with the intracellular parasite *Leishmania.* In the murine model of infection and using *Leishmania major*, it has been shown, as already mentioned, that promastigotes infect macrophages and neutrophils that are localized near the site of inoculation. Promastigotes are phagocytosed by macrophages mainly through CR3 [104], which permits parasites to enter to this host cell without activating it [107]. Interestingly, the infection with *Leishmania* downregulates the capacity of macrophages to produce IL-12. Even the stimulation of macrophages with IFN-γ/LPS does not

*Phlebotomus* transmits this pathology in Africa, Asia, and Europe [101, 102].

as well as free amastigotes and in this form the life cycle continues.

*3.1.3. Interaction of Leishmania major with macrophages and DC*

*3.1.1. Generalities of Leishmania*

*3.1.2. Leishmania life cycle*

Finally, these receptors can recognize (and opsonize) pathogens and the responses to these events are phagocytosis for antigen uptake, cell migration, cell adhesion, inhibition of cytokine production, and interaction between DC and T lymphocytes [95]. In conclusion, CLRs are key participants in the immune response that spot important signals of PAMPs, DAMPs, and TAMPs with which immune cells (e. g., dendritic cells) sense and recognize the environment. Its interactions and intersections trigger, adapt, and regulate immune responses [96].

In addition to the PRRs just mentioned, it is important to note that some orphan receptors have been described for which a ligand has not been found, as well as the family of ALR intracellular receptors (AIM2-like receptors) and another family of lectins (I-lectins) Siglecs (sialic acid binding Ig-like lectins) [97].

#### **3. Role of dendritic cells in the infection with parasites**

Due to a wide variety of functions that dendritic cells display both in the innate immune response as well as in the adaptive immune response, they are key participants in the defense against parasites. DC have the capacity to recognize different molecules in the surface of parasites and are efficient phagocytes; thus, several intracellular parasites reside inside DC. Once DC phagocytose intracellular parasites, they can exert their microbicidal capacities, although it has been shown that they are not as efficient in the destruction of microorganisms as other phagocytes such as macrophages and neutrophils. Once internalized, DC process antigens for presentation to T cells. DC have the unique property to migrate to regional lymph nodes where they activate naïve T cells, as well as produce cytokines and participate in the modulation of the immune response, the amplification of the innate immune response, and can also participate in immunological tolerance.

Protozoan infections that persist in urban environments including leishmaniasis, Chagas disease, malaria, and zoonotic diseases such as toxoplasmosis are a matter of great concern due to their prevalence, morbidity, and mortality [98]. Our best hope to counteract them is the development of new and innovative technologies. For this development, the better understanding of the biology of these parasites and their interaction with their host is of outmost importance. We chose the above-mentioned diseases and analyzed their interaction with DC that are one of the most important participants of the immune response.

#### **3.1. Interaction of dendritic cells with** *Leishmania*

#### *3.1.1. Generalities of Leishmania*

on CD14+ dDCs in dermal layers of the skin and has specificity for mannose and all Lewis type carbohydrates (Lewis A, B, X, and Y) [87]. This receptor is often endosialin with the MR (CD206) and shares mannose specificity [88]. DCIR (for DC immunoreceptor) (CLEC4a) has broad carbohydrate specificity for mannose and fucose [89, 90] and has been shown to participate in T cell responses. Different from other CLRs, DCIR contains an ITIM motif and, upon triggering with Abs, inhibits the production of inflammatory cytokines and, thus, has been associated with homeostatic control and control of inflammation [91–93]. Also, it has been shown that DCIR can participate in the capture of HIV-1 and promote infection in trans

Finally, these receptors can recognize (and opsonize) pathogens and the responses to these events are phagocytosis for antigen uptake, cell migration, cell adhesion, inhibition of cytokine production, and interaction between DC and T lymphocytes [95]. In conclusion, CLRs are key participants in the immune response that spot important signals of PAMPs, DAMPs, and TAMPs with which immune cells (e. g., dendritic cells) sense and recognize the environment. Its interactions and intersections trigger, adapt, and regulate immune

In addition to the PRRs just mentioned, it is important to note that some orphan receptors have been described for which a ligand has not been found, as well as the family of ALR intracellular receptors (AIM2-like receptors) and another family of lectins (I-lectins) Siglecs

Due to a wide variety of functions that dendritic cells display both in the innate immune response as well as in the adaptive immune response, they are key participants in the defense against parasites. DC have the capacity to recognize different molecules in the surface of parasites and are efficient phagocytes; thus, several intracellular parasites reside inside DC. Once DC phagocytose intracellular parasites, they can exert their microbicidal capacities, although it has been shown that they are not as efficient in the destruction of microorganisms as other phagocytes such as macrophages and neutrophils. Once internalized, DC process antigens for presentation to T cells. DC have the unique property to migrate to regional lymph nodes where they activate naïve T cells, as well as produce cytokines and participate in the modulation of the immune response, the amplification of the innate immune response, and can also

Protozoan infections that persist in urban environments including leishmaniasis, Chagas disease, malaria, and zoonotic diseases such as toxoplasmosis are a matter of great concern due to their prevalence, morbidity, and mortality [98]. Our best hope to counteract them is the development of new and innovative technologies. For this development, the better understanding of the biology of these parasites and their interaction with their host is of outmost importance. We chose the above-mentioned diseases and analyzed their interaction with DC

**3. Role of dendritic cells in the infection with parasites**

that are one of the most important participants of the immune response.

T cells from human immature monocyte-derived DCs [94].

and in cis of autologous CD4+

(sialic acid binding Ig-like lectins) [97].

participate in immunological tolerance.

responses [96].

54 Dendritic Cells

*Leishmania* is an obligate intracellular parasite that presents two morphological stages: the flagellated promastigote that is found in the salivary glands of the insect vector and the aflagellated amastigote that is the intracellular form found in the vertebrate host. This genus of parasites is constituted by diverse species that are morphologically indistinguishable and are grouped in three subgenera: *Leishmania*, *Viannia*, and *Sauroleishmania*. The species that cause infection in humans and other mammals are found in the subgenus *Leishmania* and *Viannia*. *Sauroleishmania* has been only found to infect some reptiles. Species belonging to *Leishmania* are characterized for having a suprapyloric development and among these are: *donovani, chagasi (infantum), major, tropica, aethiopica, mexicana (pifanoi), amazonensis,* and *venezuelensis.* On the other hand, the species of the subgenus *Viannia* have a peripyloric development and are *braziliensis, guayanensis, peruviana,* and *panamensis. Leishmania* is transmitted by Diptera belonging to the family Psychodidae, specifically, by females of the genus *Lutzomyia* and *Phlebotomus* [99, 100]*. Lutzomyia* is the transmitter of leishmaniasis in America, and *Phlebotomus* transmits this pathology in Africa, Asia, and Europe [101, 102].

#### *3.1.2. Leishmania life cycle*

*Leishmania* life cycle starts when the insect vector feeds blood from the vertebrate host and inoculates promastigotes in the superior dermis [103]. Then, promastigotes are recognized through different receptors such as CR3 [104], C-type lectin receptors, and FcγR and are phagocytosed by dermal macrophages, where they transform to amastigotes [105] and also infect neutrophils. Thanks to a series of events such as the inhibition of phagocytosis, resistance to microbicidal mechanisms, and inhibition of host cells apoptosis, amastigotes manage to survive inside macrophages and duplicate until they lyse them and infect new surrounding cells, such as dendritic cells. If the parasite is not able to inhibit the different microbicidal mechanisms of macrophages, they will be able to destroy them mainly through the production of nitric oxide and induce the activation and recruitment of proinflammatory cells such as cutaneous mast cells, neutrophils, and inflammatory monocytes that lead to the development of a focus of chronic inflammation in the site of infection, which will be evident in the patient [105, 106]. The female sand fly when ingests blood from an infected host draws infected cells as well as free amastigotes and in this form the life cycle continues.

#### *3.1.3. Interaction of Leishmania major with macrophages and DC*

One of the most studied interactions of DC with a parasite is the interaction with the intracellular parasite *Leishmania.* In the murine model of infection and using *Leishmania major*, it has been shown, as already mentioned, that promastigotes infect macrophages and neutrophils that are localized near the site of inoculation. Promastigotes are phagocytosed by macrophages mainly through CR3 [104], which permits parasites to enter to this host cell without activating it [107]. Interestingly, the infection with *Leishmania* downregulates the capacity of macrophages to produce IL-12. Even the stimulation of macrophages with IFN-γ/LPS does not elicit the production of IL-12 when cells are infected with *L. major* [108]. Once promastigotes enter to macrophages without activating them, they differentiate into amastigotes and start dividing in the parasitophorous vacuoles. Then, amastigotes are released to the extracellular milieu where they are phagocytosed by neighboring cells such as DC. DC phagocytose amastigotes mainly through FcγRI and FcγRIII, inducing DC maturation, migration to lymph nodes, and IL-12 production [109]. It has also been shown that *Leishmania-*infected DC upregulate the levels of costimulatory molecules such as CD40, CD54, CD80, and CD86, as well as of MHCII; that is, the maturation of DC enables them to initiate the activation of T lymphocytes [110]. Other authors have demonstrated that during the course of chronic infection of C57BL/6 mice with *L. major,* the main producers of iNOS are inflammatory DC, which are recruited in a CCR2-dependent manner and the induction of iNOS depends on the development of a local Th1 microenvironment [111]. In addition to the analysis of the infection of murine DC with *L. major*, other authors have shown that in the case of human DC infected with *L. major* metacyclic promastigotes, the production of high amounts of IL-12 needs the interaction of CD40-CD40L, although infected DC are able to produce some IL-12. Also, the infection of human DC with *L. major* promastigotes does not inhibit the process of maturation [112].

have shown that the interaction of *L. mexicana* and its principal host cells, macrophages and DC, are substantially different as compared to what has been observed with the *L. major* model. It has been observed that in DC infected with *L. mexicana,* the parasite manages to be internalized without the initiation of cell maturation or the production of IL-12. Although the infection inhibits IL-12 production, *L. mexicana* does not eliminate the capacity of DC to produce it and, indeed, when an external stimulus such as LPS is used, infected DC are capable of producing and secreting IL-12. In addition it was observed that the internalization of the parasite is independent of opsonization [118]. In relation to the recognition of *L. mexicana* by DC, the information about the receptors involved is scarce. On one hand, it has been reported that DC-SIGN is capable of binding *L. mexicana* LPG [119]. Recently, our group showed that DC-SIGN participates in an important manner in the internalization of *L. mexicana* promastigotes since the blockade of the receptor with a specific antibody diminished significantly the interaction of monocyte-derived dendritic cells with *L. mexicana* promastigotes [120]. Using the same strategy of blocking DC-SIGN with an antibody, its role in the infection of DC with *L. pifanoi* amastigotes was shown to be relevant since it dramatically diminished the interac-

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 57

It has been observed that DC can interact with both *L. infantum* y *L. pifanoi* amastigotes and promastigotes through DC-SIGN and that it binds more avidly the infective metacyclic forms. Interestingly, the interaction of DC with *L. major* metacyclic promastigotes does not depend on DC-SIGN [122]. Also, it has been shown that plasmacytoid DC do not internalize *L. infantum* promastigotes, although contact of the parasites with these cells induces the secretion of IFNα/β, but not of IL-12 [123]. Also, it has been described that in the early stages of *Leishmania* infection, the inflammatory milieu that is produced is ideal for the induction of monocytes

The molecular mechanisms involved in the modulation of DC during the infection with *Leishmania* have not been fully analyzed. In the murine model of infection with *L. major*, it has been clearly established that susceptible mice (Balb/c) mount a Th2-type response that enables them to eliminate the parasite while resistant mice (C57/BL6) mount a Th1 response that permits the elimination of the parasite. In contrast, C57/BL6 mice infected with *L. mexicana* metacyclic promastigotes do not resolve infection and it becomes chronic, what has been associated with a decrease in the recruitment of monocytes, a reduction in inducible nitric oxide synthase (NOS2) synthesis in moDC along with a reduction in the migration to the lymph node, which results in an insufficient activation of a Th1 response [124]. *Leishmania* parasites possess an extraordinary capacity to manipulate host cells. In particular, it has been shown that the infection of murine DC with *L. mexicana* promastigotes rapidly affects DC molecular mechanisms necessary for the development of a protective immune response, among them, an increase in tyrosine phosphatases, which translates in an inactivation of mitogen-activated protein kinases (MAPK), and decrease in the translocation of transcription factors such as

*3.1.7. Molecular mechanisms involved in the modulation of DC by Leishmania*

tion of DC with amastigotes [121].

toward Tip-DC.

*3.1.6. Interaction of DC with other species of Leishmania*

#### *3.1.4. Role of DC in the adaptive immune response against Leishmania major*

Once DC capture *Leishmania* parasites, they migrate to the lymph nodes were they activate naïve CD4 and CD8 T lymphocytes in order for them to respond specifically against the parasite with an immune response dominated by the presence of IFN-γ and cytotoxic T lymphocytes species specific in what has been called a type Th1/Tc1 immune response. This type of response permits mice to control infection and eliminate the parasite [113]. IL-12 producing DC have been observed until week 4 postinfection with a peak in week 6 just before the Th1/Tc1 IFN-γ-producing response develops completely [114]. Nevertheless, the reason for the delay in DC maturation still remains to be clarified. Iborra and colleagues have described a route that attempts to understand this delay in the maturation of DC after *Leishmania* infection. They found that *L. major* parasites secrete a soluble factor that binds to the soluble macrophage c-type lectin receptor (Mincle) of DC, which inhibits its maturation. They showed that Mincle deficiency favored stronger DC activation represented by a higher expression of costimulatory molecules, migration to dLNs and priming of a Th1 response. Thus, mice deficient in Mincle receptor are capable of controlling parasite replication and indeed had smaller lesions [115]. It has been shown that in the infection of mice with *L. major* metacyclic promastigotes, Langerhans cells induce the activation of regulatory T lymphocytes [116]. Murine CD103+ dermal DC have been shown to be responsible of inducing a protective immune response against *L. major* since mice lacking this DC subtype develop an immune response dominated by regulatory and Th2 lymphocytes infection [117].

#### *3.1.5. Interaction of DC with L. mexicana*

While *L. major* is an etiologic agent of cutaneous leishmaniasis (CL) in the Mediterranean region, *L. mexicana* is in Mexico and Central America. Although both species cause CL, the case of *L. mexicana* is of particular interest due to the fact that this species can cause localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). Different studies have shown that the interaction of *L. mexicana* and its principal host cells, macrophages and DC, are substantially different as compared to what has been observed with the *L. major* model. It has been observed that in DC infected with *L. mexicana,* the parasite manages to be internalized without the initiation of cell maturation or the production of IL-12. Although the infection inhibits IL-12 production, *L. mexicana* does not eliminate the capacity of DC to produce it and, indeed, when an external stimulus such as LPS is used, infected DC are capable of producing and secreting IL-12. In addition it was observed that the internalization of the parasite is independent of opsonization [118]. In relation to the recognition of *L. mexicana* by DC, the information about the receptors involved is scarce. On one hand, it has been reported that DC-SIGN is capable of binding *L. mexicana* LPG [119]. Recently, our group showed that DC-SIGN participates in an important manner in the internalization of *L. mexicana* promastigotes since the blockade of the receptor with a specific antibody diminished significantly the interaction of monocyte-derived dendritic cells with *L. mexicana* promastigotes [120]. Using the same strategy of blocking DC-SIGN with an antibody, its role in the infection of DC with *L. pifanoi* amastigotes was shown to be relevant since it dramatically diminished the interaction of DC with amastigotes [121].

#### *3.1.6. Interaction of DC with other species of Leishmania*

elicit the production of IL-12 when cells are infected with *L. major* [108]. Once promastigotes enter to macrophages without activating them, they differentiate into amastigotes and start dividing in the parasitophorous vacuoles. Then, amastigotes are released to the extracellular milieu where they are phagocytosed by neighboring cells such as DC. DC phagocytose amastigotes mainly through FcγRI and FcγRIII, inducing DC maturation, migration to lymph nodes, and IL-12 production [109]. It has also been shown that *Leishmania-*infected DC upregulate the levels of costimulatory molecules such as CD40, CD54, CD80, and CD86, as well as of MHCII; that is, the maturation of DC enables them to initiate the activation of T lymphocytes [110]. Other authors have demonstrated that during the course of chronic infection of C57BL/6 mice with *L. major,* the main producers of iNOS are inflammatory DC, which are recruited in a CCR2-dependent manner and the induction of iNOS depends on the development of a local Th1 microenvironment [111]. In addition to the analysis of the infection of murine DC with *L. major*, other authors have shown that in the case of human DC infected with *L. major* metacyclic promastigotes, the production of high amounts of IL-12 needs the interaction of CD40-CD40L, although infected DC are able to produce some IL-12. Also, the infection of human DC with *L. major* promastigotes does not inhibit the process of maturation [112].

Once DC capture *Leishmania* parasites, they migrate to the lymph nodes were they activate naïve CD4 and CD8 T lymphocytes in order for them to respond specifically against the parasite with an immune response dominated by the presence of IFN-γ and cytotoxic T lymphocytes species specific in what has been called a type Th1/Tc1 immune response. This type of response permits mice to control infection and eliminate the parasite [113]. IL-12 producing DC have been observed until week 4 postinfection with a peak in week 6 just before the Th1/Tc1 IFN-γ-producing response develops completely [114]. Nevertheless, the reason for the delay in DC maturation still remains to be clarified. Iborra and colleagues have described a route that attempts to understand this delay in the maturation of DC after *Leishmania* infection. They found that *L. major* parasites secrete a soluble factor that binds to the soluble macrophage c-type lectin receptor (Mincle) of DC, which inhibits its maturation. They showed that Mincle deficiency favored stronger DC activation represented by a higher expression of costimulatory molecules, migration to dLNs and priming of a Th1 response. Thus, mice deficient in Mincle receptor are capable of controlling parasite replication and indeed had smaller lesions [115]. It has been shown that in the infection of mice with *L. major* metacyclic promastigotes, Langerhans cells induce the activation of regulatory T lympho-

protective immune response against *L. major* since mice lacking this DC subtype develop an

While *L. major* is an etiologic agent of cutaneous leishmaniasis (CL) in the Mediterranean region, *L. mexicana* is in Mexico and Central America. Although both species cause CL, the case of *L. mexicana* is of particular interest due to the fact that this species can cause localized cutaneous leishmaniasis (LCL) and diffuse cutaneous leishmaniasis (DCL). Different studies

immune response dominated by regulatory and Th2 lymphocytes infection [117].

dermal DC have been shown to be responsible of inducing a

*3.1.4. Role of DC in the adaptive immune response against Leishmania major*

cytes [116]. Murine CD103+

56 Dendritic Cells

*3.1.5. Interaction of DC with L. mexicana*

It has been observed that DC can interact with both *L. infantum* y *L. pifanoi* amastigotes and promastigotes through DC-SIGN and that it binds more avidly the infective metacyclic forms. Interestingly, the interaction of DC with *L. major* metacyclic promastigotes does not depend on DC-SIGN [122]. Also, it has been shown that plasmacytoid DC do not internalize *L. infantum* promastigotes, although contact of the parasites with these cells induces the secretion of IFNα/β, but not of IL-12 [123]. Also, it has been described that in the early stages of *Leishmania* infection, the inflammatory milieu that is produced is ideal for the induction of monocytes toward Tip-DC.

#### *3.1.7. Molecular mechanisms involved in the modulation of DC by Leishmania*

The molecular mechanisms involved in the modulation of DC during the infection with *Leishmania* have not been fully analyzed. In the murine model of infection with *L. major*, it has been clearly established that susceptible mice (Balb/c) mount a Th2-type response that enables them to eliminate the parasite while resistant mice (C57/BL6) mount a Th1 response that permits the elimination of the parasite. In contrast, C57/BL6 mice infected with *L. mexicana* metacyclic promastigotes do not resolve infection and it becomes chronic, what has been associated with a decrease in the recruitment of monocytes, a reduction in inducible nitric oxide synthase (NOS2) synthesis in moDC along with a reduction in the migration to the lymph node, which results in an insufficient activation of a Th1 response [124]. *Leishmania* parasites possess an extraordinary capacity to manipulate host cells. In particular, it has been shown that the infection of murine DC with *L. mexicana* promastigotes rapidly affects DC molecular mechanisms necessary for the development of a protective immune response, among them, an increase in tyrosine phosphatases, which translates in an inactivation of mitogen-activated protein kinases (MAPK), and decrease in the translocation of transcription factors such as NF-κB and AP-1. In addition, parasites also modulate DC maturation markers decreasing the surface expression of antigen-presenting and costimulatory molecules [125]. Our group has worked for several years in the modulation of DC by *L. mexicana*. We have shown that LPG purified from *L. mexicana* promastigotes induces a major secretion of IL-12 and NF-κB translocation in human DC as compared with monocytes [126]. We also showed that the infection of murine DC with *L. mexicana* amastigotes downregulates NOS2 and thus diminishes NO production [127]. On the other hand, we have also shown that the infection of human DC with *L. mexicana* amastigotes and promastigotes inhibits the activation of MAPK JNK and p38, and the infection of human DC with *L. mexicana* amastigotes activates AKT during camptothecininduced apoptosis [128, 129].

of high amounts of IFN-γ [134, 135]. It has been previously showed that DC pulsed with *T. gondii* antigens elicit protective immunity against chronic toxoplasmosis in mice [136, 137].

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 59

DC are crucial participants in the immune response against *T. gondii* and one of the leading roles that they play in the production of IL-12, which, as previously mentioned, promotes the production of IFN-γ and thus deviates the immune response toward a Th1. DC recognize diverse *T. gondii* molecules; in particular, it has been shown that a soluble parasite extract (STAg) has a major capacity of eliciting IL-12 from splenic DC as compared to other PAMPs such as LPS and CpG oligonucleotides [138]. The production of IL-12 induced by *T. gondii* in DC is dependent on MyD88, an adaptor molecule in TLR signaling pathways, and the chemokine receptor CCR5, since the production of IL-12 decreases dramatically in mice lacking MyD88 or CCR5 [139]. Interestingly, CCR5 in DC is induced with cyclophilin-18 from *T. gondii* [139]. The participation of MyD88 in the induction of IL-12 by *T. gondii* presupposes the recognition by TLRs. Indeed, it has been shown a profilin-like protein, which is not required for the intracellular growth of *T. gondii*, but is indispensable for host cell invasion and active egress from cells [139], was identified as a ligand of TLR11 and the profilin-like protein is also recognized by TLR-12 [62], and is critical for IL-12 production, especially in plasmacytoid DCs (pDCs) [140]. TLR11 has been localized intracellularly associated with the nucleic acid-sensing TLR trafficking protein UNC93B1.52. A mutation in this protein impedes TLR intracellular trafficking, which has been shown to cause a reduction in IL-12 production in mice infected intraperitoneally with *Toxoplasma* bradyzoites and increases susceptibility to

Both cyclophilin-18 and the profilin-like protein stimulated IL-12 production in CD8α+

and CD8α− DC. Although humans do not express either TLR11 or TLR12, human monocytes produce proinflammatory cytokines in response to *T. gondii* infection, suggesting that other TLRs in humans recognize different compartments of *T. gondii* to produce IL-12 in antigenpresenting cells. Additionally, DC also produce chemokines such as CCL2 and CXCL2 upon recognition of parasite components including virulence factors [143]. These chemokines

Albeit not demonstrated specifically in DC, other TLRs, such as TLR2, can also be activated in response to *Toxoplasma* [145]. TLR2 and TLR4 both signal after binding *Toxoplasma* glycosylphosphatidylinositol (GPI) anchors [146]. However, single absence of either TLR2 or

It is possible that DCs can directly act as effector cells to eliminate *Toxoplasma* as suggested by their ability to display oxygen-dependent microbicidal activity after IFN-γ activation [148]. Moreover, plasmacytoid DCs (pDCs) have been shown to be efficient at autophagy

TLR4 in DC did not reduce the production of IL-12 in response to STAg [147].

monocytes and neutrophils to the infection site [144].

DC

**3.3. Interaction of DC with** *T. gondii*

*3.3.1. Recognition of T. gondii by DC*

infection [141, 142].

induce the migration of Ly6ChighCCR2+

*3.3.2. Effector functions of DC against T. gondii*

In addition to the modulation of DC biology exerted by *Leishmania* that has just been described, another intracellular parasite whose interaction with DC has been deeply studied is *Toxoplasma gondii.*

#### **3.2. Dendritic cells in the infection with** *Toxoplasma gondii*

#### *3.2.1. Generalities of T. gondii*

*Toxoplasma gondii* is an intracellular parasite that causes toxoplasmosis, and it can be hosted by diverse warm-blooded animals and is present in two interconvertible stages: the lytic, invasive, and active tachyzoites and the slow-growing, encysted bradyzoites. The oocysts present in the definitive host, a feline, are highly infective and long-lived and are shed in the feces for a limited time [130]. The infection initiates with direct contact with oocysts or by consumption of undercooked meat containing bradyzoite cysts. Bradyzoite cysts convert to tachyzoites in the small intestine of the intermediate host and can infect almost all nucleated cells. Here, they replicate within a parasitophorous vacuole (PV), egress by lysing the cell, and infect neighboring cells. Tachyzoites elicit a potent immune response that eliminates most parasites. However, some tachyzoites can evade this response, convert back to bradyzoites, and persist mostly in nonreplicative cells such as those in the brain or heart of their intermediate host [131].

#### *3.2.2. Immune response to T. gondii*

*Toxoplasma* orchestrates a carefully balanced string of events between various cell types including neutrophils, DCs, and macrophages upon first encountering the host innate immune defense. A complex network of molecular signaling pathways leads to the activation and regulation of cytokines and ultimately to the production of effector molecules [132]. Acquired resistance to *T. gondii* infection is mediated by a mucosal and systemic Th1 cellular immunity [133]. The deviation to a Th1 response depends enormously on the production of IL-12 by different cells such as conventional DCs, macrophages, and pDCs. Parasite infection causes damage to the intestinal epithelium resulting in the translocation of microflora and subsequent MyD88-dependent signaling and IL-12 production. IL-12 triggers the proliferation of NK cells, CD4 T cells, and CD8 T cells, which mediate cytotoxicity and the production of high amounts of IFN-γ [134, 135]. It has been previously showed that DC pulsed with *T. gondii* antigens elicit protective immunity against chronic toxoplasmosis in mice [136, 137].

#### **3.3. Interaction of DC with** *T. gondii*

#### *3.3.1. Recognition of T. gondii by DC*

NF-κB and AP-1. In addition, parasites also modulate DC maturation markers decreasing the surface expression of antigen-presenting and costimulatory molecules [125]. Our group has worked for several years in the modulation of DC by *L. mexicana*. We have shown that LPG purified from *L. mexicana* promastigotes induces a major secretion of IL-12 and NF-κB translocation in human DC as compared with monocytes [126]. We also showed that the infection of murine DC with *L. mexicana* amastigotes downregulates NOS2 and thus diminishes NO production [127]. On the other hand, we have also shown that the infection of human DC with *L. mexicana* amastigotes and promastigotes inhibits the activation of MAPK JNK and p38, and the infection of human DC with *L. mexicana* amastigotes activates AKT during camptothecin-

In addition to the modulation of DC biology exerted by *Leishmania* that has just been described, another intracellular parasite whose interaction with DC has been deeply studied

*Toxoplasma gondii* is an intracellular parasite that causes toxoplasmosis, and it can be hosted by diverse warm-blooded animals and is present in two interconvertible stages: the lytic, invasive, and active tachyzoites and the slow-growing, encysted bradyzoites. The oocysts present in the definitive host, a feline, are highly infective and long-lived and are shed in the feces for a limited time [130]. The infection initiates with direct contact with oocysts or by consumption of undercooked meat containing bradyzoite cysts. Bradyzoite cysts convert to tachyzoites in the small intestine of the intermediate host and can infect almost all nucleated cells. Here, they replicate within a parasitophorous vacuole (PV), egress by lysing the cell, and infect neighboring cells. Tachyzoites elicit a potent immune response that eliminates most parasites. However, some tachyzoites can evade this response, convert back to bradyzoites, and persist mostly in nonreplicative cells such as those in the brain or heart of their intermedi-

*Toxoplasma* orchestrates a carefully balanced string of events between various cell types including neutrophils, DCs, and macrophages upon first encountering the host innate immune defense. A complex network of molecular signaling pathways leads to the activation and regulation of cytokines and ultimately to the production of effector molecules [132]. Acquired resistance to *T. gondii* infection is mediated by a mucosal and systemic Th1 cellular immunity [133]. The deviation to a Th1 response depends enormously on the production of IL-12 by different cells such as conventional DCs, macrophages, and pDCs. Parasite infection causes damage to the intestinal epithelium resulting in the translocation of microflora and subsequent MyD88-dependent signaling and IL-12 production. IL-12 triggers the proliferation of NK cells, CD4 T cells, and CD8 T cells, which mediate cytotoxicity and the production

**3.2. Dendritic cells in the infection with** *Toxoplasma gondii*

induced apoptosis [128, 129].

*3.2.1. Generalities of T. gondii*

is *Toxoplasma gondii.*

58 Dendritic Cells

ate host [131].

*3.2.2. Immune response to T. gondii*

DC are crucial participants in the immune response against *T. gondii* and one of the leading roles that they play in the production of IL-12, which, as previously mentioned, promotes the production of IFN-γ and thus deviates the immune response toward a Th1. DC recognize diverse *T. gondii* molecules; in particular, it has been shown that a soluble parasite extract (STAg) has a major capacity of eliciting IL-12 from splenic DC as compared to other PAMPs such as LPS and CpG oligonucleotides [138]. The production of IL-12 induced by *T. gondii* in DC is dependent on MyD88, an adaptor molecule in TLR signaling pathways, and the chemokine receptor CCR5, since the production of IL-12 decreases dramatically in mice lacking MyD88 or CCR5 [139]. Interestingly, CCR5 in DC is induced with cyclophilin-18 from *T. gondii* [139]. The participation of MyD88 in the induction of IL-12 by *T. gondii* presupposes the recognition by TLRs. Indeed, it has been shown a profilin-like protein, which is not required for the intracellular growth of *T. gondii*, but is indispensable for host cell invasion and active egress from cells [139], was identified as a ligand of TLR11 and the profilin-like protein is also recognized by TLR-12 [62], and is critical for IL-12 production, especially in plasmacytoid DCs (pDCs) [140]. TLR11 has been localized intracellularly associated with the nucleic acid-sensing TLR trafficking protein UNC93B1.52. A mutation in this protein impedes TLR intracellular trafficking, which has been shown to cause a reduction in IL-12 production in mice infected intraperitoneally with *Toxoplasma* bradyzoites and increases susceptibility to infection [141, 142].

Both cyclophilin-18 and the profilin-like protein stimulated IL-12 production in CD8α+ DC and CD8α− DC. Although humans do not express either TLR11 or TLR12, human monocytes produce proinflammatory cytokines in response to *T. gondii* infection, suggesting that other TLRs in humans recognize different compartments of *T. gondii* to produce IL-12 in antigenpresenting cells. Additionally, DC also produce chemokines such as CCL2 and CXCL2 upon recognition of parasite components including virulence factors [143]. These chemokines induce the migration of Ly6ChighCCR2+ monocytes and neutrophils to the infection site [144]. Albeit not demonstrated specifically in DC, other TLRs, such as TLR2, can also be activated in response to *Toxoplasma* [145]. TLR2 and TLR4 both signal after binding *Toxoplasma* glycosylphosphatidylinositol (GPI) anchors [146]. However, single absence of either TLR2 or TLR4 in DC did not reduce the production of IL-12 in response to STAg [147].

#### *3.3.2. Effector functions of DC against T. gondii*

It is possible that DCs can directly act as effector cells to eliminate *Toxoplasma* as suggested by their ability to display oxygen-dependent microbicidal activity after IFN-γ activation [148]. Moreover, plasmacytoid DCs (pDCs) have been shown to be efficient at autophagy [149], a process known to eliminate *Toxoplasma* in primed macrophages and to involve the family of p47 GTPases [150]. The various subsets of DC possibly recognize either direct infection with *Toxoplasma* or sense parasite products differently, and are thus important mediators of parasitic elimination and facilitators for the development of an efficient adaptive immune response. Conventional CD11c+ DC have been shown to play key roles in host resistance to *Toxoplasma* bradyzoite cysts administered i.p. [151, 152].

hepatocytes, thus, reducing parasite loads in hepatocytes. There is evidence that suggests

participate in the process of antigen cross presentation throughout the infection [171, 172]. In

TNF-α. Finally, the stimulation of DC with *Plasmodium* antigens also induces their migration

Apart from the interaction of DC with protozoan parasites that has been discussed, we chose

*Trichinella spiralis* is a parasitic helminth that belongs to the group of nematodes. Its biological cycle begins when a mammal (usually mouse, rat, pig, and human) ingests raw or undercooked meat containing cysts (encysted larvae). As it passes through gastric acid and pepsin, the larva is released from the cyst and invades the mucosa of the small intestine, where it matures to the sexually differentiated adult state that initiates reproduction [178]. After 1 week, females release larvae, which migrate to skeletal striated muscle where they encyst and the cycle closes when cysts are ingested by another mammal [178]. In order for *T. spiralis* to remain for long periods in the muscle, the parasite must have mechanisms to evade the immune response and inhibit tissue inflammation. It has been described that *T. spiralis* muscle larvae have structural carbohydrates on their surface that contribute to the activation of the immune response that results in Th2/anti-inflammatory response [179]. It has been shown that *T. spiralis* glycans affect the anti-inflammatory environment and can interfere with the development of inflammatory diseases [180]. On the other hand, *T. spiralis* muscle larvae excrete a molecular complex called excretory-secretory antigen (ES L1) that has been shown to alter DC maturation [180]. In addition, immature DC resulting from the exposure to ES L1 induce a Th2 and regulatory response

cell population [179]. Thanks to these two mechanisms, the induction of an anti-inflammatory response and the inhibition of DC maturation, *T. spiralis* survives as long as it is the muscular

Dendritic cells represent a wide constellation of cells that perform crucial roles in the immune response covering from recognition and phagocytosis, to antigen processing and presentation

the same subtype of DC responsible for the activity of TCD8+

presentation of *Plasmodium* antigens by DC to TCD4+

**3.5. Interaction of** *Trichinella spiralis* **with DC**

and produces IL-12, IL-6, and TNF-α, thus inducing TCD4+

) spleen DC and (CD8α+

There is evidence that, of these two subtypes, only the CD8α−CD11b+

*Trichinella spiralis* as an example of the interaction of a helminth with DC.

with the production of IL-10 and TGF-β, but without increasing CD4+

larva without inducing inflammation or an adequate immune response.

CD11b-DC located in the peripheral lymph nodes near the mosquito inoculation site are

cells is associated with the production of IFN-γ, which is induced by two

cells, in the acute phase of the infection, while the CD8α+

CD11b− and CD8α−CD11b+

cells, in different study models, it has been shown that the

cells [165–168]. The protective

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491

cells expresses MHC-II, CD40, and CD80

CD25+

Foxp3+

effector T

cells to express IL-2, IFN-γ, and

) D C) [169, 170].

CD11b−DC

61

DC are responsible for

CD8+

response of TCD8+

**4. Conclusion**

subtypes of mature (CD40+

relation to the activation of TCD4+

of DC to lymphoid organs [173–177].

the activation of TCD4+

#### **3.4. Role of DC in the infection with** *Plasmodium*

#### *3.4.1. Plasmodium life cycle*

Malaria is a disease caused by the blood protozoan of the genus *Plasmodium* about which there have been described five species capable of infecting humans that are *P. falciparum, P. vivax, P. malariae, P. knowlesi,* and *P. ovale* [153]. The life cycle of this parasite starts when a hematophagous female mosquito of the genus *Anopheles* introduces its proboscis, containing infective sporozoites into the mammalian host. There is evidence that once the sporozoites have been inoculated, they can remain on the skin for hours and slowly release into the blood [154, 155]. Once sporozoites reach the bloodstream, they migrate to the liver where they infect hepatocytes and transform into merozoites that infect red blood cells. Some of these merozoites transform into male and female gametocytes to finally complete their cycle within the mosquito's digestive tract [156, 157].

#### *3.4.2. Interaction of DC with Plasmodium*

Several studies have revealed that DC play an important role during *Plasmodium* life cycle, as well as in the pathophysiology and outcome of the disease. Although *Plasmodium* does not infect DC, it has been shown that the interaction of DC with infected erythrocytes has an effect on DC functions. In particular, it has been shown that erythrocytes infected with *P. falciparum* and co-cultured with human DC manage to induce in them an arrest in the process of maturation, thus inhibiting their ability to stimulate and activate T lymphocytes; however, the effect is dependent on the parasite: DC ratio [158, 159]. Also, during the acute phase of infection with *Plasmodium*, there is an increase in BDCA3+ DC, but not in CD1c+ DC, which correlates with a severe presentation of the disease [160, 161]. Other DC populations that change during *Plasmodium* infection are pDC (HLA-DR+ CD123+ ): mDC (HLA-DR+ CD11c+ ). It has been reported that the ratio of pDC:mDC diminishes in patients suffering from the acute phase of *P. vivax* infection. In addition to this decrease, there also exists an arrest in DC maturation demonstrated by a reduction in CD86 in patients infected with *P. vivax* and a decrease in CD83 and HLA-DR in individuals in the acute phase of infection with *P. vivax* and *P. falciparum*. This diminution of CD functions in these infections is accompanied by an increase in the number of cells that die by apoptosis, as well as by the decrease in their ability to capture, mature, and present antigens to T cells [162–164].

Other research groups have addressed the role of DC in the induction of the response of T and B cells in *Plasmodium* infection. It has been shown that TCD8+ cells, previously activated by DC, exert their cytotoxic effect by inducing death of *P. vivax* sporozoites housed in hepatocytes, thus, reducing parasite loads in hepatocytes. There is evidence that suggests CD8+ CD11b-DC located in the peripheral lymph nodes near the mosquito inoculation site are the same subtype of DC responsible for the activity of TCD8+ cells [165–168]. The protective response of TCD8+ cells is associated with the production of IFN-γ, which is induced by two subtypes of mature (CD40+ ) spleen DC and (CD8α+ CD11b− and CD8α−CD11b+ ) D C) [169, 170]. There is evidence that, of these two subtypes, only the CD8α−CD11b+ DC are responsible for the activation of TCD4+ cells, in the acute phase of the infection, while the CD8α+ CD11b−DC participate in the process of antigen cross presentation throughout the infection [171, 172]. In relation to the activation of TCD4+ cells, in different study models, it has been shown that the presentation of *Plasmodium* antigens by DC to TCD4+ cells expresses MHC-II, CD40, and CD80 and produces IL-12, IL-6, and TNF-α, thus inducing TCD4+ cells to express IL-2, IFN-γ, and TNF-α. Finally, the stimulation of DC with *Plasmodium* antigens also induces their migration of DC to lymphoid organs [173–177].

Apart from the interaction of DC with protozoan parasites that has been discussed, we chose *Trichinella spiralis* as an example of the interaction of a helminth with DC.

#### **3.5. Interaction of** *Trichinella spiralis* **with DC**

*Trichinella spiralis* is a parasitic helminth that belongs to the group of nematodes. Its biological cycle begins when a mammal (usually mouse, rat, pig, and human) ingests raw or undercooked meat containing cysts (encysted larvae). As it passes through gastric acid and pepsin, the larva is released from the cyst and invades the mucosa of the small intestine, where it matures to the sexually differentiated adult state that initiates reproduction [178]. After 1 week, females release larvae, which migrate to skeletal striated muscle where they encyst and the cycle closes when cysts are ingested by another mammal [178]. In order for *T. spiralis* to remain for long periods in the muscle, the parasite must have mechanisms to evade the immune response and inhibit tissue inflammation. It has been described that *T. spiralis* muscle larvae have structural carbohydrates on their surface that contribute to the activation of the immune response that results in Th2/anti-inflammatory response [179]. It has been shown that *T. spiralis* glycans affect the anti-inflammatory environment and can interfere with the development of inflammatory diseases [180]. On the other hand, *T. spiralis* muscle larvae excrete a molecular complex called excretory-secretory antigen (ES L1) that has been shown to alter DC maturation [180]. In addition, immature DC resulting from the exposure to ES L1 induce a Th2 and regulatory response with the production of IL-10 and TGF-β, but without increasing CD4+ CD25+ Foxp3+ effector T cell population [179]. Thanks to these two mechanisms, the induction of an anti-inflammatory response and the inhibition of DC maturation, *T. spiralis* survives as long as it is the muscular larva without inducing inflammation or an adequate immune response.

#### **4. Conclusion**

[149], a process known to eliminate *Toxoplasma* in primed macrophages and to involve the family of p47 GTPases [150]. The various subsets of DC possibly recognize either direct infection with *Toxoplasma* or sense parasite products differently, and are thus important mediators of parasitic elimination and facilitators for the development of an efficient adap-

Malaria is a disease caused by the blood protozoan of the genus *Plasmodium* about which there have been described five species capable of infecting humans that are *P. falciparum, P. vivax, P. malariae, P. knowlesi,* and *P. ovale* [153]. The life cycle of this parasite starts when a hematophagous female mosquito of the genus *Anopheles* introduces its proboscis, containing infective sporozoites into the mammalian host. There is evidence that once the sporozoites have been inoculated, they can remain on the skin for hours and slowly release into the blood [154, 155]. Once sporozoites reach the bloodstream, they migrate to the liver where they infect hepatocytes and transform into merozoites that infect red blood cells. Some of these merozoites transform into male and female gametocytes to finally complete their cycle within the

Several studies have revealed that DC play an important role during *Plasmodium* life cycle, as well as in the pathophysiology and outcome of the disease. Although *Plasmodium* does not infect DC, it has been shown that the interaction of DC with infected erythrocytes has an effect on DC functions. In particular, it has been shown that erythrocytes infected with *P. falciparum* and co-cultured with human DC manage to induce in them an arrest in the process of maturation, thus inhibiting their ability to stimulate and activate T lymphocytes; however, the effect is dependent on the parasite: DC ratio [158, 159]. Also, during the acute phase of

correlates with a severe presentation of the disease [160, 161]. Other DC populations that

It has been reported that the ratio of pDC:mDC diminishes in patients suffering from the acute phase of *P. vivax* infection. In addition to this decrease, there also exists an arrest in DC maturation demonstrated by a reduction in CD86 in patients infected with *P. vivax* and a decrease in CD83 and HLA-DR in individuals in the acute phase of infection with *P. vivax* and *P. falciparum*. This diminution of CD functions in these infections is accompanied by an increase in the number of cells that die by apoptosis, as well as by the decrease in their ability

Other research groups have addressed the role of DC in the induction of the response of

vated by DC, exert their cytotoxic effect by inducing death of *P. vivax* sporozoites housed in

DC have been shown to play key roles in host

DC, but not in CD1c+

): mDC (HLA-DR+

CD123+

DC, which

CD11c+ ).

cells, previously acti-

tive immune response. Conventional CD11c+

*3.4.1. Plasmodium life cycle*

60 Dendritic Cells

mosquito's digestive tract [156, 157].

*3.4.2. Interaction of DC with Plasmodium*

infection with *Plasmodium*, there is an increase in BDCA3+

change during *Plasmodium* infection are pDC (HLA-DR+

to capture, mature, and present antigens to T cells [162–164].

T and B cells in *Plasmodium* infection. It has been shown that TCD8+

**3.4. Role of DC in the infection with** *Plasmodium*

resistance to *Toxoplasma* bradyzoite cysts administered i.p. [151, 152].

Dendritic cells represent a wide constellation of cells that perform crucial roles in the immune response covering from recognition and phagocytosis, to antigen processing and presentation to naïve T cells and immune tolerance. Due to this wide array of functions, they constitute a bridge that connects the innate immune response with the adaptive and are very important against parasites. DC are able to recognize diverse PAMPs present in parasites through different PRRs such TLRs, CLRs, NLRs, and RLRs, some of which, upon binding their respective ligand, induce phagocytosis and/or signal for the production of different molecules. Parasitic infections cause great morbidity and mortality. For the majority of them, there are no vaccines and the treatments that are not always effective. The better understanding and gaining of knowledge on the biology of parasites and their interaction with the immune system, in particular with DC due to the important role that play in the immune responses, will permit the development of new strategies and drugs to effectively treat the pertaining diseases mentioned in this work.

[3] Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proceedings of the National Academy of

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 63

[4] Steinman RM. Dendritic cells: From the fabric of immunology. Clinical and Investigative

[5] Nussenzweig MC, Steinman RM, Unkeless JC, Witmer MD, Gutchinov B, Cohn ZA. Studies of the cell surface of mouse dendritic cells and other leukocytes. The Journal of

[6] Nussenzweig MC, Steinman RM, Witmer MD, Gutchinov B. A monoclonal antibody specific for mouse dendritic cells. Proceedings of the National Academy of Sciences of

[7] Bevan MJ. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. The Journal of

[8] Rock KL. The ins and outs of cross-presentation. Nature Immunology. 2003;**4**(10):941-943 [9] Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity.

[10] Shortman K, Liu YJ. Mouse and human dendritic cell subtypes. Nature Reviews.

[11] Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development.

[12] Shortman K, Lahoud MH, Caminschi I. Improving vaccines by targeting antigens to dendritic cells. Experimental & Molecular Medicine. 2009;**41**(2):61-66. DOI: 10.3858/

[13] Heath WR, Carbone FR. Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nature Immunology. 2009;**10**(12):1237-1244. DOI: 10.1038/ni.1822 [14] Steinman RM, Idoyaga J. Features of the dendritic cell lineage. Immunological Reviews.

[15] Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology. 2013;**31**:563-604. DOI: 10.1146/annurev-immunol-

[16] Sehgal K, Dhodapkar KM, Dhodapkar MV.Targeting human dendritic cells *in situ* to improve vaccines. Immunology Letters. 2014;**162**(1PtA):59-67. DOI: 10.1016/j.imlet.2014.07.004 [17] Schnitzer JK, Berzel S, Fajardo-Moser M, Remer KA, Moll H. Fragments of antigen-loaded dendritic cells (DC) and DC-derived exosomes induce protective immunity against *Leishmania major*. Vaccine. 2010;**28**(36):5785-5793. DOI: 10.1016/j.vaccine.2010.06.077

Sciences of the United States of America. 1978;**75**:5132-5136

Medicine. 2004;**27**(5):231-236

Experimental Medicine. 1981;**154**:168-187

the United States of America. 1982;**79**:161-165

Experimental Medicine. 1976;**143**(5):1283-1288

Immunology. 2002;**2**(3):151-161

emm.2<IP_ADDRESS>

020711-074950

2014;**40**:642-656. DOI: 10.1016/j.immuni.2014.04.016

Nature Reviews. Immunology. 2007;**7**(1):19-30

2010;**234**(1):5-17. DOI: 10.1111/j.0105-2896.2009.00888.x

#### **Financial support**

This work was supported by grant IN225116 from Papiit, DGAPA, UNAM to LGK.

#### **Author details**

Laila Gutiérrez-Kobeh1 \*, Jorge Rodríguez-González1,2, Jesús Argueta-Donohué3 , Rosalino Vázquez-López4 and Arturo A. Wilkins-Rodríguez1

\*Address all correspondence to<EMAIL_ADDRESS>
1 Research Unit UNAM-INC, Research Division, School of Medicine, National Autonomous University of Mexico-National Institute of Cardiology, Mexico City, Mexico

2 Posgrado en Ciencias Biológicas, Facultad de Medicina, Unidad de Posgrado, Ciudad Universitaria, Mexico City, Mexico

3 National Institute of Psychiatry, Mexico City, Mexico

4 Microbiology Department, CICSA, Health Science Faculty, Universidad Anáhuac México Norte, Huixquilucan, Mexico

#### **References**

[3] Steinman RM, Witmer MD. Lymphoid dendritic cells are potent stimulators of the primary mixed leukocyte reaction in mice. Proceedings of the National Academy of Sciences of the United States of America. 1978;**75**:5132-5136

to naïve T cells and immune tolerance. Due to this wide array of functions, they constitute a bridge that connects the innate immune response with the adaptive and are very important against parasites. DC are able to recognize diverse PAMPs present in parasites through different PRRs such TLRs, CLRs, NLRs, and RLRs, some of which, upon binding their respective ligand, induce phagocytosis and/or signal for the production of different molecules. Parasitic infections cause great morbidity and mortality. For the majority of them, there are no vaccines and the treatments that are not always effective. The better understanding and gaining of knowledge on the biology of parasites and their interaction with the immune system, in particular with DC due to the important role that play in the immune responses, will permit the development of new strategies and drugs to effectively treat the pertaining diseases men-

This work was supported by grant IN225116 from Papiit, DGAPA, UNAM to LGK.

and Arturo A. Wilkins-Rodríguez1

University of Mexico-National Institute of Cardiology, Mexico City, Mexico

1 Research Unit UNAM-INC, Research Division, School of Medicine, National Autonomous

2 Posgrado en Ciencias Biológicas, Facultad de Medicina, Unidad de Posgrado, Ciudad

4 Microbiology Department, CICSA, Health Science Faculty, Universidad Anáhuac México

[1] Langerhans P. Uber die nerven der menschlichen haut. Archives of Pathological

[2] Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. The Journal of Experimental

\*, Jorge Rodríguez-González1,2, Jesús Argueta-Donohué3

,

tioned in this work.

62 Dendritic Cells

**Financial support**

**Author details**

Laila Gutiérrez-Kobeh1

Rosalino Vázquez-López4

Universitaria, Mexico City, Mexico

Anatomy. 1868;**44**:325-337

Medicine. 1973;**137**:1142-1162

Norte, Huixquilucan, Mexico

**References**

\*Address all correspondence to<EMAIL_ADDRESS>
3 National Institute of Psychiatry, Mexico City, Mexico

[18] Fajardo-Moser M, Berzel S, Moll H. Mechanisms of dendritic cell-based vaccination against infection. International Journal of Medical Microbiology. 2008;**298**(1-2):11-20

[31] Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. Flt3 ligand regulates dendritic cell development from Flt3 lymphoid and myeloid-committed progenitors to Flt3 dendritic cells *in vivo*. The Journal of Experimental Medicine. 2003;**198**(2):305-313. DOI:

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 65

[32] Waskow C, Liu D-JG, Guermonprez P, Ginhoux F, Merad M, Shengelia T, et al. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral

[33] Kingston D, Schmid MA, Onai N, Obata-Onai A, Baumjohann D, Manz MG. The concerted action of GM-CSF and Flt3-ligand on *in vivo* dendritic cell homeostasis. Blood.

[34] Lee J, Breton G, Oliveira TY, Zhou YJ, Aljoufi A, Puhr S, et al. Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. The Journal of

[35] Collin M, Mcgovern N, Haniffa M. Human dendritic cell subsets. Immunology. 2013;

[36] Schreibelt G, Tel J, Kwinten HEW, Sliepen J, Benitez-Ribas D, Carl G, et al. Toll-like receptor expression and function in human dendritic cell subsets: Implications for dendritic cell-based anti-cancer immunotherapy. Cancer Immunology, Immunotherapy.

[37] Banchereau J, Klechevsky E, Schmitt N, Morita R, Palucka K, Ueno H. Harnessing human dendritic cell subsets to design novel vaccines. Annals of the New York Academy

[38] Auffray C, Sieweke MH, Geiss-Mann F. Blood monocytes: Development, heterogeneity, and relationship with dendritic cells. Annual Review of Immunology. 2009;**27**:669-692

[39] Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nature

[40] Lande R, Gilliet M. Plasmacytoid dendritic cells: Key players in the initiation and regulation of immune responses. Annals of the New York Academy of Sciences. 2010;**1183**:89-103

[41] Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Plasmacytoid dendritic cells: Recent progress and open questions. Annual Review of Immunology. 2011;**29**:163-183

[42] Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, et al. Alloantigenpresenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nature

[43] Fallarino F, Asselin-Paturel C, Vacca C, Bianchi R, Gizzi S, Fioretti MC, et al. Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to cd200 receptor engagement. Journal of Immunology.

Experimental Medicine. 2015;**212**(3):385-399. DOI: 10.1084/jem.20141442

of Sciences. 2009;**1174**:24-32. DOI: 10.1111/j.1749-6632.2009.04999.x

lymphoid tissues. Nature Immunology. 2008;**9**(6):676-683. DOI: 10.1038/ni.1615

2009;**114**:835-843. DOI: 10.1182/blood-2009-02-206318

2010;**59**:1573-1582. DOI: 10.1007/s00262-010-0833-1

**140**:22-30. DOI: 10.1111/imm.12117

Reviews. Immunology. 2015;**15**:471-485

Immunology. 2006;**7**:652-662

2004;**173**:3748-3754

10.1084/jem.20030323

[31] Karsunky H, Merad M, Cozzio A, Weissman IL, Manz MG. Flt3 ligand regulates dendritic cell development from Flt3 lymphoid and myeloid-committed progenitors to Flt3 dendritic cells *in vivo*. The Journal of Experimental Medicine. 2003;**198**(2):305-313. DOI: 10.1084/jem.20030323

[18] Fajardo-Moser M, Berzel S, Moll H. Mechanisms of dendritic cell-based vaccination against infection. International Journal of Medical Microbiology. 2008;**298**(1-2):11-20 [19] Berberich C, Ramírez-Pineda JR, Hambrecht C, Alber G, Skeiky YA, Moll H. Dendritic cell (DC)-based protection against an intracellular pathogen is dependent upon DC-derived IL-12 and can be induced by molecularly defined antigens. Journal of Immunology.

[20] Matos I, Mizenina O, Lubkin A, Steinman RM, Idoyaga J. Targeting *Leishmania major* antigens to dendritic cells in vivo induces protective immunity. PLoS One. 2013;**8**:e67453.

[21] Kastenmüller W, Kastenmüller K, Kurts C, Seder RA. Dendritic cell-targeted vaccineshope or hype? Nature Reviews. Immunology. 2014;**14**:705-711. DOI: 10.1038/nri3727 [22] Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, et al. Clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science. 2006;**311**:83-87.

[23] Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, et al. *In vivo* analysis of dendritic cell development and homeostasis. Science. 2009;**324**(5952):392-397.

[24] Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;**327**(5966):656-661. DOI: 10.1126/

[25] Naik SH, Sathe P, Park HY, Metcalf D, Proietto AI, Dakic A, et al. Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived *in*

*vitro* and *in vivo*. Nature Immunology. 2007;**8**(11):1217-1226. DOI: 10.1038/ni1522 [26] Onai N, Obata-Onai A, Schmid MA, Manz MG. Flt3 in regulation of type I interferonproducing cell and dendritic cell development. Annals of the New York Academy of

[27] Onai N, Obata-Onai A, Schmid MA, Ohteki T, Jarrossay D, Manz MG. Identification of clonogenic common Flt3 M-CSFR plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nature Immunology. 2007;**8**(11):1207-1216. DOI: 10.1038/ni1518

[28] Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, Hashimoto D, et al. The origin and development of nonlymphoid tissue CD103+ DCs. The Journal of Experimental

[29] Onai N, Kurabayashi K, Hosoi-Amaike M, Toyama-Sorimachi N, Matsushima K, Inaba K, et al. A clonogenic progenitor with prominent plasmacytoid dendritic cell developmen-

[30] McKenna HJ, Stocking KL, Miller RE, Brasel K, De Smedt T, Maraskovsky E, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells,

tal potential. Immunity. 2013;**38**(5):943-957. DOI: 10.1016/j.immuni.2013.04.006

Sciences. 2007;**1106**:253-261. DOI: 10.1196/annals.1392.015

Medicine. 2009;**206**(13):3115-3130. DOI: 10.1084/jem.20091756

dendritic cells, and natural killer cells. Blood. 2000;**95**(11):3489-3497

2003;**170**(6):3171-3179

64 Dendritic Cells

DOI: 10.1371/journal.pone.0067453

DOI: 10.1126/science.1117729

DOI: 10.1126/science.1170540

science.1178331

[44] Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nature Immunology. 2011;**12**:870-878

[57] Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Whynot J, Novitskaya I, Cardinale I, et al. Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. Journal of Allergy and Clinical Immunology. 2007;**119**:

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 67

[58] Schraml BU, Reis e Sousa C. Defining dendritic cells. Current Opinion in Immunology.

[59] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system.

[60] Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;

[61] Iwasaki A, Medzhitov R. Toll-like receptor control of theadaptive immune responses.

[62] Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science. 2005;

[63] Zhang DK, Zhang GL, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, et al. A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004;**303**:

[64] Guven-Maiorov E, Keskin O, Gursoy A, Nussinov R. A structural view of negative regulation of the Toll-like receptormediated inflammatory pathway. Biophysical Journal.

[65] Sasai M, Yamamoto M. Pathogen recognition receptors: Ligands and signaling pathways by Toll-like receptors. International Reviews of Immunology. 2013;**32**(2):116-133. DOI:

[66] Quinn SR, O'Neill LA. A trio of microRNAs that control Toll-like receptor signalling.

[67] Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annual Review of

[69] Broz P, Monack DM. Newly described pattern recognition receptors team up against intracellular pathogens. Nature Reviews. Immunology. 2013;**13**(8):551-565. DOI: 10.1038/

[70] Lee SMY, Yip TF, Yan S, Jin DY, Wei HL, Guo RT, et al. Recognition of double-stranded RNA and regulation of interferon pathway by toll-like receptor 10. Frontiers in

[71] Mills KHG. TLR-dependent T cell activation in autoimmunity. Nature Reviews. Immu-

Immunology. 2006;**24**:353-389. DOI: 10.1146/annurev.immunol.24.021605.090552 [68] Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Inter-

International Immunology. 2011;**23**(7):421-425. DOI: 10.1093/intimm/dxr03

national Immunology. 2009;**21**(4):317-337. DOI: 10.1093/intimm/dxp017

Immunology. 2018;**9**(516):1-15. DOI: 10.3389/fimmu.2018.00516

nology. 2011;**11**(12):807-822. DOI: 10.1038/nri3095

Nature Immunology. 2015;**16**(4):343-353. DOI: 10.1038/ni.3123.Control

1210-1217. DOI: 10.1016/j.jaci.2007.03.006

2015;**32**:13-20. DOI: 10.1016/j.coi.2014.11.001

Nature Immunology. 2004;**5**:987-995

10.3109/08830185.2013.774391

**308**(5728):1626-1629. DOI: 10.1126/science.1109893

2015;**109**(6):1214-1226. DOI: 10.1016/j.bpj.2015.06.048

**124**:783-801

1522-1526

nri3479

[57] Guttman-Yassky E, Lowes MA, Fuentes-Duculan J, Whynot J, Novitskaya I, Cardinale I, et al. Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. Journal of Allergy and Clinical Immunology. 2007;**119**: 1210-1217. DOI: 10.1016/j.jaci.2007.03.006

[44] Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, et al. Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nature

[45] O'Keeffe M, Mok WH, Radford KJ. Human dendritic cell subsets and function in health

[46] Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, Lanzavecchia A, et al. Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts

[47] Matsui T, Connolly JE, Michnevitz M, Chaussabel D, Yu C-I, Glaser C, et al. CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and

[48] Bryant C, Fromm PD, Kupresanin F, Clark G, Lee K, Clarke C, et al. A CD2 highexpressing stress-resistant human plasmacytoid dendritic-cell subset. Immunology and

[49] Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunology.

[50] Geissmann F, Auffray C, Palframan R, Wirrig C, Ciocca A, Campisi L, et al. Blood monocytes: Distinct subsets, how they relate to dendritic cells, and their possible roles in the

[51] Copin R, De Baetselier P, Carlier Y, Letesson JJ, Muraille E. MyD88-dependent activation of B220-CD11b+LY-6C+ dendritic cells during *Brucella melitensis* infection. Journal of

[52] Bosschaerts T, Guilliams M, Stijlemans B, Morias Y, Engel D, Tacke F, et al. Tip-DC development during parasitic infection is regulated by IL-10 and requires CCL2/CCR2, IFN-γ and MyD88 signaling. PLoS Pathogens. 2010;**6**(8):e1001045. DOI: 10.1371/journal.

[53] Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;**116**(16):e74-e80. DOI: 10.1182/

[54] Haniffa M, Shin A, Bigley V, Mcgovern N, Teo P, See P, et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103 nonlymphoid dendritic cells. Immunity. 2012;**37**:60-73. DOI: 10.1016/j.immuni.2012.04.012

[55] Watchmaker PB, Lahl K, Lee M, Baumjohann D, Morton J, Kim SJ, et al. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nature Immunology. 2013;**15**:98-108. DOI: 10.1038/ni.2768

[56] Segura E, Touzot M, Bohineust A, Cappuccio A, Chiocchia G, Hosmalin A, et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 2013;**38**:336-348.

regulation of T-cell responses. Immunology and Cell Biology. 2008;**86**:398-408

and disease. Cellular and Molecular Life Sciences. 2015;**72**:4309-4325

of type I interferon. Nature Medicine. 1999;**5**:919-923

functions. Journal of Immunology. 2009;**182**(11):6815-6823

Immunology. 2011;**12**:870-878

66 Dendritic Cells

Cell Biology. 2016;**94**(5):447-457

2006;**7**:311-317. DOI: 10.1038/ni1309

Immunology. 2007;**178**:5182-5191

DOI: 10.1016/j.immuni.2012.10.018

ppat.1001045

blood-2010-02-258558

[72] Bruns AM, Horvath CM. Activation of RIG-I-like receptor signal transduction. Critical Reviews in Biochemistry and Molecular Biology. 2012;**47**(2):194-206. DOI: 10.3109/10409238.2011.630974

[85] Do Y, Park CG, Kang Y, Park SH, Lynch RM, Lee H, et al. Broad T cell immunity to the LcrV virulence protein is induced by targeted delivery to DEC205/CD205 positive mouse dendritic cells. European Journal of Immunology. 2008;**38**:20-29. DOI: 10.1002/

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 69

[86] Shrimpton RE, Butler M, Morel A, Eren E, Hue SS, Ritter MA. CD205 (DEC-205): A recognition receptor for apoptotic and necrotic self. Molecular Immunology. 2009;**46**:

[87] Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that

[88] Martinez-Pomares L. The mannose receptor. Journal of Leukocyte Biology. 2012;**92**:

[89] Bates EE, Fournier N, Garcia E, Valladeau J, Durand I, Pin JJ, et al. APCs express DCIR, a novel C-type lectin surface receptor containing an immunoreceptor tyrosine-based

[90] Lee RT, Hsu TL, Huang SK, Hsieh SL, Wong CH, Lee YC. Survey of immune-related, mannose/fucose-binding C-type lectin receptors reveals widely divergent sugar-binding

[91] Kanazawa N, Okazaki T, Nishimura H, Tashiro K, Inaba K, Miyachi Y. DCIR acts as an inhibitory receptor depending on its immunoreceptor tyrosine-based inhibitory motif.

[92] Meyer-Wentrup F, Cambi A, Joosten B, Looman MW, de Vries IJ, Figdor CG, et al. DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine produc-

[93] Meyer-Wentrup F, Benitez-Ribas D, Tacken PJ, Punt CJ, Figdor CG, de Vries IJ, et al. Targeting DCIR on human plasmacytoid dendritic cells results in antigen presentation

[94] Lambert AA, Gilbert C, Richard M, Beaulieu AD, Tremblay MJ. The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways. Blood. 2008;**112**(4):1299-1307. DOI: 10.1182/

[95] Mayer S, Raulf MK, Lepenies B. C-type lectins: Their network and roles in pathogen recognition and immunity. Histochemistry and Cell Biology. 2017;**147**(2):223-237. DOI:

[96] Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: A cell biological perspective. Annual Review of Immunology. 2015;**33**(1):257-290. DOI:

eji.200737799.Broad

1177-1186

1229-1239. DOI: 10.1016/j.molimm.2008.11.016

specificities. Glycobiology. 2011;**21**:512-520

supports primary immune responses. Cell. 2000;**100**:575-585

inhibitory motif. Journal of Immunology. 1999;**163**:1973-1983

The Journal of Investigative Dermatology. 2002;**118**:261-266

tion. Journal of Leukocyte Biology. 2008;**85**:518-525

blood-2008-01-136473

10.1007/s00418-016-1523-7

10.1146/annurev-immunol-032414-112240

and inhibits IFN-α production. Blood. 2008;**111**:4245-4253

[85] Do Y, Park CG, Kang Y, Park SH, Lynch RM, Lee H, et al. Broad T cell immunity to the LcrV virulence protein is induced by targeted delivery to DEC205/CD205 positive mouse dendritic cells. European Journal of Immunology. 2008;**38**:20-29. DOI: 10.1002/ eji.200737799.Broad

[72] Bruns AM, Horvath CM. Activation of RIG-I-like receptor signal transduction. Critical Reviews in Biochemistry and Molecular Biology. 2012;**47**(2):194-206. DOI:

[73] Dixit E, Kagan JC. Intracellular pathogen detection by RIG-I-like receptors. Advances in

[74] Corridoni D, Simmons A. Innate immune receptors for cross-presentation: The expanding role of NLRs. Molecular Immunology. 2017;**S0161-5890**(17):30591-30596. DOI: 10.

[75] Liu D, Rhebergen AM, Eisenbarth SC. Licensing adaptive immunity by NOD-like receptors. Frontiers in Immunology. 2013;**4**(Dec):486. DOI: 10.3389/fimmu.2013.00486

[76] Krishnaswamy JK, Chu T, Eisenbarth SC. Beyond pattern recognition: NOD-like receptors in dendritic cells. Trends in Immunology. 2013;**34**(5):224-233. DOI: 10.1016/j.it.2012.

[77] Ellwanger K, Becker E, Kienes I, Sowa A, Postma Y, Cardona Y, et al. The NLR family pyrin domain-containing 11 protein contributes to the regulation of inflammatory signaling. The Journal of Biological Chemistry. 2018;**293**(8):2701-2710. DOI: 10.1074/jbc.

[78] Krishnaswamy JK, Singh A, Gowthaman U, Wu R, Gorrepati P, Sales Nascimento M, et al. Coincidental loss of DOCK8 function in NLRP10-deficient and C3H/HeJ mice results in defective dendritic cell migration. Proceedings of the National Academy of Sciences of the United States of America. 2015;**112**(10):3056-3061. DOI: 10.1073/pnas.1501554112 [79] Arthur JC, Lich JD, Ye Z, Allen IC, Gris D, Wilson JE, et al. Cutting edge: NLRP12 controls dendritic and myeloid cell migration to affect contact hypersensitivity. Journal of

[80] Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and Langerhans cells. Nature Reviews. Immunology. 2002;**2**:77-84. DOI: 10.1038/nri723 [81] Dambuza IM, Brown GD. C-type lectins in immunity: Recent developments. Current

[82] Brown GD, Willment JA, Whitehead L. C-type lectins in immunity and homeostasis. Nature Reviews. Immunology. 2018;**18**(6):374-389. DOI: 10.1038/s41577-018-0004-8 [83] Fresno C, Iborra S, Saz-Leal P, Martínez-López M, Sancho D. Flexible signaling of myeloid C-type lectin receptors in immunity and inflammation. Frontiers in Immunology.

[84] van Dinther D, Stolk DA, van de Ven R, van Kooyk Y, de Gruijl TD, den Haan JMM. Targeting C-type lectin receptors: A high-carbohydrate diet for dendritic cells to improve cancer vaccines. Journal of Leukocyte Biology. 2017;**102**(4):1017-1034. DOI: 10.1189/

Immunology. 2010;**185**(8):4515-4519. DOI: 10.4049/jimmunol.1002227

Opinion in Immunology. 2015;**32**:21-27. DOI: 10.1016/j.coi.2014.12.002

2018;**9**(Apr):1-13. DOI: 10.3389/fimmu.2018.00804

Immunology. 2013;**117**:99-125. DOI: 10.1016/B978-0-12-410524-9.00004-9

10.3109/10409238.2011.630974

1016/j.molimm.2017.11.028

12.003

68 Dendritic Cells

RA117.000152

jlb.5MR0217-059RR

[97] Pillai S, Netravali AI, Cariappa A, Matto H. Siglecs and immune regulation. Annual Review of Immunology. 2012;**30**:357-392. DOI: 10.1146/annurev-immunol-020711-075018.Siglecs

2006;**203**(1):177-188. Available from: http://www.jem.org/lookup/doi/10.1084/jem.

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 71

[110] Von Stebut E, Belkaid Y, Jakob T, Sacks DL, Udey MC. Uptake of *Leishmania major* amastigotes results in skin derived dendritic cells: Implications for the initiation of anti-*Leishmania* immunity. The Journal of Experimental Medicine. 1998;**188**(8):1547-1552

[111] Marovich M, McDowell MA, Thomas EK, Nutman TB. IL-12p70 production by *Leishmania major*-harboring human dendritic cells is a CD40/CD40 ligand-dependent process. Journal of Immunology. 2000;**164**(11):5858-5865. Available from: http://www.

[112] De Trez C, Magez S, Akira S, Ryffel B, Carlier Y, Muraille E. iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic *Leishmania major* infection phase of C57BL/6 resistant mice. PLoS Pathogens. 2009;**5**(6):e1000494.

[113] von Stebut E. Parasites dampen dendritic cell activation to ensure their survival. Trends

[114] Belkaid Y, Mendez S, Lira R, Kadambi N, Milon G, Sacks D. A natural model of *Leishmania major* infection reveals a prolonged "silent" phase of parasite amplification in the skin before the onset of lesion formation and immunity. Journal of Immunology. 2000;**165**(2):969-977. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.

[115] Iborra S, Martínez-López M, Cueto FJ, Conde-Garrosa R, Del Fresno C, Izquierdo HM, et al. *Leishmania* uses Mincle to target an inhibitory ITAM signaling pathway in dendritic cells that dampens adaptive immunity to infection. Immunity. 2016;**45**(4):788-801.

[116] Kautz-Neu K, Noordegraaf M, Dinges S, Bennett CL, John D, Clausen BE, et al. Langerhans cells are negative regulators of the anti-*Leishmania* response. The Journal of Experimental Medicine. 2011;**208**(5):885-891. Available from: http://www.jem.org/

[117] Martínez-López M, Iborra S, Conde-Garrosa R, Sancho D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against *Leishmania major* infection in mice. European Journal of Immunology. 2015;**45**(1):119-129.

[118] Bennett CL, Misslitz A, Colledge L, Aebischer T, Clare Blackburn C. Silent infection of bone marrow-derived dendritic cells by *Leishmania mexicana* amastigotes. European

[119] Appelmelk BJ, van Die I, van Vliet SJ, Vandenbroucke-Grauls CMJE, Geijtenbeek TBH, van Kooyk Y. Cutting edge: Carbohydrate profiling identifies new pathogens that interact with dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells. Journal

in Parasitology. 2016;**33**(2):78-80. DOI: 10.1016/j.pt.2016.12.001

Available from: http://www.ncbi.nlm.nih.gov/pubmed/27742545

Available from: http://doi.wiley.com/10.1002/eji.201444651

Journal of Immunology. 2001;**31**(3):876-883

20052288

165.2.969

ncbi.nlm.nih.gov/pubmed/10820265

DOI: 10.1371/journal.ppat.1000494

lookup/doi/10.1084/jem.20102318

2006;**203**(1):177-188. Available from: http://www.jem.org/lookup/doi/10.1084/jem. 20052288

[110] Von Stebut E, Belkaid Y, Jakob T, Sacks DL, Udey MC. Uptake of *Leishmania major* amastigotes results in skin derived dendritic cells: Implications for the initiation of anti-*Leishmania* immunity. The Journal of Experimental Medicine. 1998;**188**(8):1547-1552

[97] Pillai S, Netravali AI, Cariappa A, Matto H. Siglecs and immune regulation. Annual Review of Immunology. 2012;**30**:357-392. DOI: 10.1146/annurev-immunol-020711-075018.Siglecs

[98] Hotez PJ. Human parasitology and parasitic diseases: Heading towards 2050. Advances in Parasitology. 2018;**100**:29-38. DOI: 10.1016/bs.apar.2018.03.002 (Epub Apr 5, 2018) [99] Godínez-Álvarez A, Ibanez-Bernal S. Catálogo de Psychodidae (diptera) de la colección de artrópodos con importancia médica del INDRE, Secretaría de Salud, México. Acta

[100] Oliveira F, de Carvalho A, de Oliveira C. Sand-fly saliva-*Leishmania*-man: The trigger

[101] Ready PD. Should sand fly taxonomy predict vectorial and ecological traits? Journal of

[102] Berman J. Recent developments in leishmaniasis: Epidemiology, diagnosis, and treatment. Current Infectious Disease Reports. 2005;**7**:33-38. DOI: 10.1007/s11908-005-0021-1

[103] Von Stebut E. Immunology of cutaneous leishmaniasis: The role of mast cells, phagocytes and dendritic cells for protective immunity. European Journal of Dermatology.

[104] Mosser DM, Edelson PJ. The mouse macrophage receptor for C3bi (CR3) is a major mechanism in the phagocytosis of *Leishmania* promastigotes. Journal of Immunology. 1985;**135**(4):2785-2789. Available from: http://www.jimmunol.org/content/135/4/2785.

[105] Chenik M, Lakhal S, Khalef NB, Zribi L, Louzir H, Dellagi K. Approaches for the identification of potential excreted/secreted proteins of *Leishmania major* parasites.

[106] Von Stebut E, Metz M, Milon G, Knop J, Maurer M. Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1alpha/beta released from neu-

[107] Schönlau F, Scharffetter-Kochanek K, Grabbe S, Pietz B, Sorg C, Sunderkötter C. In experimental leishmaniasis deficiency of CD18 results in parasite dissemination associated with altered macrophage functions and incomplete Th1 cell response. European Journal of Immunology. 2000;**30**(9):2729-2740. DOI: 10.1002/1521-4141(200009)30:9<2729::AID-IMMU2

[108] Belkaid Y, Butcher B, Sacks DL. Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: Selective impairment of IL-12 induction in *Leishmania-*infected cells. European Journal of Immunology. 1998;**28**(4):1389-1400.

[109] Woelbing F, Kostka SL, Moelle K, Belkaid Y, Sunderkoetter C, Verbeek S, et al. Uptake of *Leishmania major* by dendritic cells is mediated by Fcγ receptors and facilitates acquisition of protective immunity. The Journal of Experimental Medicine.

trophils recruited by mast cell-derived TNFalpha. Blood. 2003;**101**:210-215

Parasitology. 2006;**132**:493-509. DOI: 10.1017/s0031182005009546

Available from: http://www.ncbi.nlm.nih.gov/pubmed/9565379

Zoologica Mexicana. 2010;**26**(1):99-121

Vector Ecology. 2011;**36**(S1):S17-S22

2007;**17**(2):115-122

abstract

70 Dendritic Cells

729>3.0.CO;2-3

trio. Frontiers in Immunology. 2013;**4**:375-382

of Immunology. 2003;**170**(4):1635-1639. Available from: http://www.jimmunol.org/cgi/ doi/10.4049/jimmunol.170.4.1635

[129] Rodríguez-González J, Wilkins-Rodríguez A, Argueta-Donohué J, Aguirre-García M, Gutiérrez-Kobeh L. *Leishmania mexicana* promastigotes down regulate JNK and p-38 MAPK activation: Role in the inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells. Experimental Parasitology. 2016;**163**:57-67. Available from:

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 73

[130] Elmore SA, Jones JL, Conrad PA, Patton S, Lindsay DS, Dubey JP. *Toxoplasma gondii:* Epidemiology, feline clinical aspects, and prevention. Trends in Parasitology.

[131] Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004;**363**:1965-1976. DOI: 10.1016/

[132] Sanecka A, Frickel EM. Use and abuse of dendritic cells by *Toxoplasma gondii*. Virulence.

[133] Denkers EY, Gazzinelli RT. Regulation and function of T-cell-mediated immunity dur-

[134] Gazzinelli RT, Hieny S, Wynn TA, Wolf S, Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proceedings of the National Academy

[135] Hunter CA, Subauste CS, Van Cleave VH, Remington JS. Production of gamma interferon by natural killer cells from *Toxoplasma gondii*-infected SCID mice: Regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infection and Immunity.

[136] Bourguin I, Moser M, Buzoni-Gatel D, Tielemans F, Bout D, Urbain J, et al. Murine dendritic cells pulsed in vitro with *Toxoplasma gondii* antigens induce protective immunity

[137] Dimier-Poisson I, Aline F, Mévélec MN, Beauvillain C, Buzoni-Gatel D, Bout D. Protective mucosal Th2 immune response against *Toxoplasma gondii* by murine mesenteric lymph node dendritic cells. Infection and Immunity. 2003;**71**:5254-5265. DOI:

[138] Aliberti J, Jankovic D, Sher A. Turning it on and off: Regulation of dendritic cell function in *Toxoplasma gondii* infection. Immunological Reviews. 2004;**201**:26-34. DOI:

[139] Plattner F, Yarovinsky F, Romero S, Didry D, Carlier MF, Sher A, et al. *Toxoplasma* profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response. Cell Host & Microbe. 2008;**3**(2):77-87. DOI: 10.1016/j.chom.

[140] Koblansky AA, Jankovic D, Oh H, Hieny S, Sungnak W, Mathur R, et al. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to *Toxoplasma gondii*.

Immunity. 2013;**38**(1):119-130. DOI: 10.1016/j.immuni.2012.09.016

ing *Toxoplasma gondii* infection. Clinical Microbiology. 1998;**11**:569-588

of Sciences of the United States of America. 1993;**90**(13):6115-6119

*in vivo*. Infection and Immunity. 1998;**66**(10):4867-4874

http://www.ncbi.nlm.nih.gov/pubmed/26777406

2010;**26**:190-196. DOI: 10.1016/j.pt.2010.01.0094

2012;**3**(7):678-689. DOI: 10.4161/viru.22833

S0140-6736(04)16412-X

1994;**62**(7):2818-2824

10.1128/IAI.71.9.5254

2008.01.001

10.1111/j.0105-2896.2004.00179.x

[129] Rodríguez-González J, Wilkins-Rodríguez A, Argueta-Donohué J, Aguirre-García M, Gutiérrez-Kobeh L. *Leishmania mexicana* promastigotes down regulate JNK and p-38 MAPK activation: Role in the inhibition of camptothecin-induced apoptosis of monocyte-derived dendritic cells. Experimental Parasitology. 2016;**163**:57-67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26777406

of Immunology. 2003;**170**(4):1635-1639. Available from: http://www.jimmunol.org/cgi/

[120] Argueta-Donohué J, Wilkins-Rodríguez AA, Aguirre-García M, Gutiérrez-Kobeh L. Differential phagocytosis of *Leishmania mexicana* promastigotes and amastigotes by monocyte-derived dendritic cells. Microbiology and Immunology. 2016;**60**(6):369-381.

[121] Colmenares M, Puig-Kröger A, Pello OM, Corbı́ AL, Rivas L. Dendritic cell (DC) specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for *Leishmania* amastigotes. The Journal of Biological Chemistry. 2002;**277**(39):36766-36769. Available from: http://

[122] Colmenares M, Corbi AL, Turco SJ, Rivas L. The dendritic cell receptor DC-SIGN discriminates among species and life cycle forms of *Leishmania*. Journal of Immunology. 2004;**172**(2):1186-1190. Available from: http://www.jimmunol.org/cgi/doi/10.4049/jimmunol.

[123] Schleicher U, Liese J, Knippertz I, Kurzmann C, Hesse A, Heit A, et al. NK cell activation in visceral leishmaniasis requires TLR9, myeloid DCs, and IL-12, but is independent of plasmacytoid DCs. The Journal of Experimental Medicine. 2007;**204**(4):893-906.

[124] Petritus PM, Manzoni-de-Almeida D, Gimblet C, Gonzalez Lombana C, Scott P. *Leishmania mexicana* induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection. PLoS Neglected Tropical

[125] Contreras I, Estrada JA, Guak H, Martel C, Borjian A, Ralph B, et al. Impact of *Leishmania mexicana* infection on dendritic cell signaling and functions. PLoS Neglected Tropical Diseases. 2014;**8**(9):e3202. Available from: http://dx.plos.org/10.1371/journal.

[126] Argueta-Donohué J, Carrillo N, Valdés-Reyes L, Zentella A, Aguirre-García M, Becker I, et al. *Leishmania mexicana*: Participation of NF-κB in the differential production of IL-12 in dendritic cells and monocytes induced by lipophosphoglycan (LPG). Experimental Parasitology. 2008;**120**(1):1-9. Available from: http://linkinghub.elsevier.

[127] Wilkins-Rodriguez AA, Escalona-Montano AR, Aguirre-Garcia M, Becker I, Gutierrez-Kobeh L. Regulation of the expression of nitric oxide synthase by *Leishmania mexicana* amastigotes in murine dendritic cells. Experimental Parasitology. 2010;**126**(3):426-434

[128] Vázquez-López R, Argueta-Donohué J, Wilkins-Rodríguez A, Escalona-Montaño A, Aguirre-García M, Gutiérrez-Kobeh L. *Leishmania mexicana* amastigotes inhibit p38 and JNK and activate PI3K/AKT: Role in the inhibition of apoptosis of dendritic cells. Parasite Immunol. 2015;**37**(11):579-589. Available from: http://www.ncbi.nlm.nih.gov/

Available from: http://www.jem.org/lookup/doi/10.1084/jem.20061293

Available from: http://doi.wiley.com/10.1111/1348-0421.12325

www.jbc.org/lookup/doi/10.1074/jbc.M205270200

doi/10.4049/jimmunol.170.4.1635

172.2.1186

72 Dendritic Cells

Diseases. 2012;**6**(10):e1858

com/retrieve/pii/S0014489408000957

pntd.0003202

pubmed/26352010

[141] Pifer R, Benson A, Sturge CR, Yarovinsky F. UNC93B1 is essential for TLR11 activation and IL-12-dependent host resistance to *Toxoplasma gondii*. Journal of Biological Chemistry. 2011;**286**:3307-3314. DOI: 10.1074/jbc.M110.171025

their Toll-like receptors. Proceedings of the National Academy of Sciences of the United

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 75

[153] WHO. World Malaria Report 2014. WHO Report. World Health Organization. ISBN

[154] Amino R, Thiberge S, Martin B, Celli S, Shorte S, Frischknecht F, et al. Quantitative imaging of *Plasmodium* transmission from mosquito to mammal. Nature Medicine.

[155] Yamauchi LM, Coppi A, Snounou G, Sinnis P. *Plasmodium* sporozoites trickle out of the

[156] Mota MM, Pradel G, Vanderberg JP, Hafalla JC, Frevert U, Nussenzweig RS, et al. Migration of through cells before infection. Science. 2001;**291**(5501):141-144

[157] Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, et al. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science.

[158] Urban BC, Ferguson DJ, Pain A, Willcox N, Plebanski M, Austyn JM, et al. *Plasmodium falciparum* infected erythrocytes modulate the maturation of dendritic cells. Nature.

[159] Elliott SR, Spurck TP, Dodin JM, Maier AG, Voss TS, Yosaatmadja F, et al. Inhibition of dendritic cell maturation by malaria is dose dependent and does not require erythro-

[160] Urban BC, Cordery D, Shafi MJ, Bull PC, Newbold CI, Williams TN, et al. The frequency of BDCA3-positive dendritic cells is increased in the peripheral circulation of Kenyan children with severe malaria. Infection and Immunity. 2006;**74**(12):6700-6706

[161] Guermonprez G, Helft J, Claser C, Deroubaix S, Karanje H, Gazumyan A, et al. Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses dur-

[162] Gonçalves RM, Salmazi KC, Santos BA, Bastos MS, Rocha SC, Boscardin SB, et al. CD4+ CD25+ Foxp3+ regulatory T cells, dendritic cells, and circulating cytokines in uncomplicated malaria: Do different parasite species elicit similar host responses? Infection and

[163] Jangpatarapongsa K, Chootong P, Sattabongkot CK, Sirichaisinthrop J, Tungpradabkul S, Hisaeda H, et al. *Plasmodium vivax* parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. European Journal of

[164] Pinzon-Charry A, Woodberry T, Kienzle V, McPhun V, Minigo G, Lampah DA, et al. Apoptosis and dysfunction of blood dendritic cells in patients with *falciparum* and *vivax*

malaria. The Journal of Experimental Medicine. 2013;**210**(8):1635-1646

cyte membrane protein 1. Infection and Immunity. 2007;**75**(7):3621-3632

ing *Plasmodium* infection. Nature Medicine. 2013;**19**(6):730-738

States of America. 2011;**108**:278-283. DOI: 10.1073/pnas.1011549108

injection site. Cellular Microbiology. 2007;**9**(5):1215-1222

978-92-4-156483-0

2006;**12**(2):220-224

2006;**313**(5791):1287-1290

Immunity. 2010;**78**(11):4763-4772

Immunology. 2008;**38**(10):2697-2705

1999;**400**(6739):73-77

their Toll-like receptors. Proceedings of the National Academy of Sciences of the United States of America. 2011;**108**:278-283. DOI: 10.1073/pnas.1011549108

[153] WHO. World Malaria Report 2014. WHO Report. World Health Organization. ISBN 978-92-4-156483-0

[141] Pifer R, Benson A, Sturge CR, Yarovinsky F. UNC93B1 is essential for TLR11 activation and IL-12-dependent host resistance to *Toxoplasma gondii*. Journal of Biological

[142] Melo MB, Kasperkovitz P, Cerny A, Könen-Waisman S, Kurt-Jones EA, Lien E, et al. UNC93B1 mediates host resistance to infection with *Toxoplasma gondii*. PLoS Pathogens.

[143] Zlotnik A, Yoshie O. Chemokines: A new classification system and their role in immu-

[144] Getts DR, Terry RL, Getts MT, Müller M, Rana S, Shrestha B, et al. Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile

[145] Mun H-S, Aosai F, Norose K, Chen M, Piao L-X, Takeuchi O, et al. TLR2 as an essential molecule for protective immunity against *Toxoplasma gondii* infection. International

[146] Debierre-Grockiego F, Campos MA, Azzouz N, Schmidt J, Bieker U, Resende MG, et al. Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from

[147] Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, Denkers EY, et al. Cutting edge: MyD88 is required for resistance to *Toxoplasma gondii* infection and regulates parasite-induced IL-12 production by dendritic cells. Journal of Immunology.

[148] Aline F, Bout D, Dimier-Poisson I. Dendritic cells as effector cells: Gamma interferon activation of murine dendritic cells triggers oxygen-dependent inhibition of *Toxoplasma gondii* replication. Infection and Immunity. 2002;**70**:2368-2374. DOI: 10.1128/

[149] Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007;**315**:1398-1401. DOI:

[150] Ling YM, Shaw MH, Ayala C, Coppens I, Taylor GA, Ferguson DJP, et al. Vacuolar and plasma membrane stripping and autophagic elimination of *Toxoplasma gondii* in primed effector macrophages. The Journal of Experimental Medicine. 2006;**203**(9):2063-2071.

[151] Liu C-H, Fan YT, Dias A, Esper L, Corn RA, Bafica A, et al. Cutting edge: Dendritic cells are essential for in vivo IL-12 production and development of resistance against

[152] Hou B, Benson A, Kuzmich L, DeFranco AL, Yarovinsky F. Critical coordination of innate immune defense against *Toxoplasma gondii* by dendritic cells responding via

*Toxoplasma gondii* infection in mice. Journal of Immunology. 2006;**177**(1):31-35

virus encephalitis. The Journal of Experimental Medicine. 2008;**205**:2319

Immunology. 2003;**15**(9):1081-1087. DOI: 10.1093/intimm/dxg10854

*Toxoplasma gondii*. Journal of Immunology. 2007;**179**(2):1129-1137

Chemistry. 2011;**286**:3307-3314. DOI: 10.1074/jbc.M110.171025

2010;**6**:e1001071. DOI: 10.1371/journal.ppat.1001071

nity. Immunity. 2000;**12**(2):121-127

74 Dendritic Cells

2002;**168**(12):5997-6001

IAI.70.5.2368-2374.2002.66

10.1126/science.113688067

DOI: 10.1084/jem.2006131868-71

[165] Bruña-Romero O, Rodriguez A. Dendritic cells can initiate protective immune responses against malaria. Infection and Immunity. 2001;**69**(8):5173-5176

[178] Kapel CMO. Host diversity and biological characteristics of the Trichinella genotypes

Role of Dendritic Cells in Parasitic Infections http://dx.doi.org/10.5772/intechopen.79491 77

[179] Cvetkovic J, Ilic N, Sofronic-Milosavljevic L, Gruden-Movsesijan A. Glycans expressed on *Trichinella spiralis* excretory-secretory antigens are important for anti-inflamatory immune response polarization. Comparative Immunology, Microbiology and Infectious

[180] Gruden-Movsesijan A, Ilic N, Colic M, Majstorovic I, Vasilev S, Radovic I, et al. The impact of *Trichinella spiralis* excretory-secretory products on dendritic cells. Comparative Immunology, Microbiology and Infectious Diseases. 2011;**34**(5):429-439. DOI: 10.1016/j.

and their effect on transmission. Veterinary Parasitology. 2000;**93**:263-278

Diseases. 2014;**37**(5-6):355-367. DOI: 10.1016/j.cimid.2014.10.004

cimid.2011.08.004

[178] Kapel CMO. Host diversity and biological characteristics of the Trichinella genotypes and their effect on transmission. Veterinary Parasitology. 2000;**93**:263-278

[165] Bruña-Romero O, Rodriguez A. Dendritic cells can initiate protective immune responses

[166] Vichchathorn P, Jenwithisuk R, Leelaudomlipi S, Tungpradabkul S, Hongeng S, Cui L, et al. Induction of specific immune responses against the *Plasmodium vivax* liver-stage via *in vitro* activation by dendritic cells. Parasitology International. 2006;**55**(3):187-193

[167] Jung S, Unutmaz D, Wong P, Sano G, De los Santos K, Sparwasser T, et al. *In vivo* depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous

[168] Radtke AJ, Kastenmüller W, Espinosa DA, Gerner MY, Tse SW, Sinnis P, et al. Lymph node resident CD8+ dendritic cells capture antigens from migratory malaria sporozoites and induce CD8+ T cell responses. PLOS Pathogens. 2015;**11**(2):e1004637. DOI:

[169] Behboudi S, Moore A, Hill AVS. Splenic dendritic cell subsets prime and boost CD8 T cells and are involved in the generation of effector CD8 T cells. Cellular Immunology.

[170] Murray SA, Mohar I, Miller JL, Brempelis KJ, Vaughan AM, Kappe SH, et al. CD40 is required for protective immunity against liver stage *Plasmodium* infection. Journal of

[171] Sponaas AM, Cadman ET, Voisine C, Harrison V, Boonstra A, O'Garra A, et al. Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-

[172] Sponaas AM, Belyaev N, Falck-Hansen M, Potocnik A, Langhorne J. Transient deficiency of dendritic cells results in lack of a merozoite surface protein 1-specific CD4 T cell response during peak *Plasmodium chabaudi* blood-stage infection. Infection and

[173] Perry JA, Rush A, Wilson RJ, Olver CS, Avery AC. Dendritic cells from malaria-infected mice are fully functional APC. Journal of Immunology. 2004;**172**(1):475-482

[174] Luyendyk J, Olivas OR, Ginger LA, Avery AC. Antigen-presenting cell function during

[175] Seixas E, Cross C, Quin S, Langhorne J. Direct activation of dendritic cells by the malaria parasite *Plasmodium chabaudi chabaudi*. European Journal of Immunology.

[176] Leisewitz AL, Rockett KA, Gumede B, Jones M, Urban B, Kwiatkowski DP. Response of the splenic dendritic cell population to malaria infection. Infection and Immunity.

[177] Amorim KN, Chagas DC, Sulczewski FB, Boscardin SB. Dendritic cells and their multiple roles during malaria infection. Journal of Immunology Research. 2016;**2016**:2926436.

*Plasmodium yoelii* infection. Infection and Immunity. 2002;**70**(6):2941-2949

specific T cells. The Journal of Experimental Medicine. 2006;**203**(6):1427-1433

against malaria. Infection and Immunity. 2001;**69**(8):5173-5176

cell-associated antigens. Immunity. 2002;**17**(2):211-220

10.1371/journal.ppat.1004637

Immunology;**194**(5):2268-2279

Immunity. 2012;**80**(12):4248-4256

2001;**31**(10):2970-2978

2004;**72**(7):4233-4239

DOI: 10.1155/2016/2926436

2004;**228**(1):15-19

76 Dendritic Cells

**Chapter 5**

**Provisional chapter**

**The Role of Dendritic Cells in Bone Loss and Repair**

**The Role of Dendritic Cells in Bone Loss and Repair**

DOI: 10.5772/intechopen.79625

The cells of innate immunity, such as neutrophils, macrophages, and dendritic cells (DCs), stuck to the bone implant walls release reactive radicals, enzymes, and chemokines, which induced subsequent bone loss. DCs do not play a big role in bone homeostasis in steady-state conditions, but could act as osteoclasts precursors in inflammation foci of bone. The potent antigen-presenting cells responsible for activation of native T cells and modulation of T cell activity through RANK/RANKL pathway and other cytokines associated with osteoclastogenesis determine critically situated at the osteoimmune interface. The titanium (Ti) and magnesium (Mg), the metallic candidate in implant, including calcium-phosphate coating formation on them by method plasma electrolytic oxidation were used to evaluate the immune-modulatory effects of DCs. The calcium-phosphate coating on metals induced mature DC (mDC) phenotype, while Ti and Mg promoted a noninflammatory environment by supporting an immature DC (iDC) phenotype based on surface marker expression, cytokine production profiles, and cell morphology. These findings have numerous therapeutic implications in addition to DC's important role in regulating innate and adaptive immunity. A direct contribution of these cells to inflammation-induced bone loss establishes DC as a promising therapeutic target, not only for

controlling inflammation but also for modulating bone destruction.

**Keywords:** osteoimmunology, dendritic cells, bone, titanium, magnesium,

There are two forms of the immune response of organism: innate and adaptive ones and dendritic cells (DC) serve as a bridge between them. The role of innate immunity cells

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Natalia G. Plekhova, Irina N. Lyapun,

Natalia G. Plekhova, Irina N. Lyapun,

http://dx.doi.org/10.5772/intechopen.79625

Dmitry Mashtalyar

Dmitry Mashtalyar

**Abstract**

biocompatibility

**1. Introduction**

Sergey Gnedenkov, Sergey Sinebryukhov and

Sergey Gnedenkov, Sergey Sinebryukhov and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **The Role of Dendritic Cells in Bone Loss and Repair The Role of Dendritic Cells in Bone Loss and Repair**

DOI: 10.5772/intechopen.79625

Natalia G. Plekhova, Irina N. Lyapun, Sergey Gnedenkov, Sergey Sinebryukhov and Dmitry Mashtalyar Natalia G. Plekhova, Irina N. Lyapun, Sergey Gnedenkov, Sergey Sinebryukhov and Dmitry Mashtalyar

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79625

#### **Abstract**

The cells of innate immunity, such as neutrophils, macrophages, and dendritic cells (DCs), stuck to the bone implant walls release reactive radicals, enzymes, and chemokines, which induced subsequent bone loss. DCs do not play a big role in bone homeostasis in steady-state conditions, but could act as osteoclasts precursors in inflammation foci of bone. The potent antigen-presenting cells responsible for activation of native T cells and modulation of T cell activity through RANK/RANKL pathway and other cytokines associated with osteoclastogenesis determine critically situated at the osteoimmune interface. The titanium (Ti) and magnesium (Mg), the metallic candidate in implant, including calcium-phosphate coating formation on them by method plasma electrolytic oxidation were used to evaluate the immune-modulatory effects of DCs. The calcium-phosphate coating on metals induced mature DC (mDC) phenotype, while Ti and Mg promoted a noninflammatory environment by supporting an immature DC (iDC) phenotype based on surface marker expression, cytokine production profiles, and cell morphology. These findings have numerous therapeutic implications in addition to DC's important role in regulating innate and adaptive immunity. A direct contribution of these cells to inflammation-induced bone loss establishes DC as a promising therapeutic target, not only for controlling inflammation but also for modulating bone destruction.

**Keywords:** osteoimmunology, dendritic cells, bone, titanium, magnesium, biocompatibility

#### **1. Introduction**

There are two forms of the immune response of organism: innate and adaptive ones and dendritic cells (DC) serve as a bridge between them. The role of innate immunity cells

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

in inflammation-induced osteoclastogenesis and subsequent bone loss is critical, thereby establishing a new paradigm of osteoimmunology [1–3]. According to the long-standing definition, septic and aseptic total joint and bone replacement loosening are two distinct conditions with little in common. Septic bone replacement loosening is driven by bacterial infection whereas aseptic loosening is caused by biomaterial wear debris released from the bearing surfaces. The initial injury to the tissue surrounding a bone implant induces an inflammatory response mediated by the cells of innate immunity, such as neutrophils, macrophages, and DCs. The cells, which are stuck to the implant walls, release reactive radicals, enzymes, and chemokines, which cause a cascade of inflammatory responses [4, 5]. The mobilization of functional activity of innate immunity cells is directed by chemokines, cytokines, and integrins. Recently, it has been recognized that the mechanisms that drive macrophage activation in septic and aseptic total joint replacement loosening resemble each other [6]. Accumulating evidence indicates that in addition to mediating bacterial recognition and the subsequent inflammatory reaction, toll-like receptors (TLRs) and their ligands, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), play a key role in wear debris-induced inflammation and cellular activation. Furthermore, metal ions released from some total joint replacements can activate TLR signaling similar to bacterial derived PAMPs [7]. Likewise, metal ions can function as haptens activating the adaptive immune system similar to bacterial derived antigens [8]. Thus, it appears that aseptic and septic joint and bone replacement loosening share similar underlying pathomechanisms. DCs derive from the mononuclear cell pool and are characterized by high expression levels of CD11c/major histocompatibility complex (MHC) II. Conventional DCs are capable of antigen presentation and reverse migration, i.e., are able to migrate to lymph nodes via afferent lymphatic vessels. Immature progenitor conventional DCs are unable to prime T cells, but are equipped with high phagocytic activity [9]. It was shown that, DCs can influence the type of immune response through the induction of regulatory mechanisms. Immature DCs express chemokine receptors (CCR-1, −2, −5, −6 and CXCR-1) and are able to migrate actively to the inflammatory focus in response to the appearance of chemokines [10]. The process of maturation of DC is initiated by various factors, including biomolecules of microorganisms, pro-inflammatory cytokines and products of necrosis of cells and tissues. Maturation of the DC is a continuous process, in which there is a decrease in the endocytic potential, the expression of antigen-recognizing receptors, while, on the opposite side, the expression of adhesion molecules CD54 and CD58 increases. This changes the structural organization of cellular organelles, increases the activity of lysosomal enzymes, there are immunoproteasomes which process the intracellular protein antigens. Fully differentiated DCs actively produce pro-inflammatory cytokines, such as IL-12alpha (IL-12p35), through which T-lymphocytes are activated, including regulatory lymphocytes [11].