the ability of the immune system to keep tolerance to commensals while remaining capable of responding to injury or infection with pathogenic microorganisms is essential for tissue homeostasis .
any disturbances in this balance either by genetic , environmental , or infectious causes can lead to chronic inflammatory and/or autoimmune diseases .
the mucosal immune system should sense pathogens versus innocuous dietary antigens or commensal microorganisms . while a strong and protective response is required to eliminate pathogens , tolerance is essential for harmless antigens or nutrients , thus avoiding inflammatory responses . during oral tolerance
systemic immune effector function including delayed type hypersensitivity response and ige antibody production are affected [ 1 , 2 ] . furthermore , intestine - resident effector cells also undergo tolerance .
impairment of oral tolerance seems to be associated with coeliac disease , characterized by an aberrant th1-mediated dth triggered by dietary gluten [ 1 , 3 ] .
similarly , ige - mediated food allergies can be derived from the break of tolerance to food antigens [ 1 , 4 ] . along the same lines ,
break of tolerance at the large intestine is thought to trigger hyperreactivity to commensal bacteria resulting in inflammatory bowel diseases , including crohn 's disease .
interestingly , tolerance to commensal flora does not exert a systemic effect [ 6 , 7 ] .
moreover , iga production is maintained , thus supporting commensalism , because of the noninflammatory properties of iga [ 8 , 9 ] .
it is well accepted that clonal deletion and/or t cell anergy are components of the mechanism of action of oral tolerance , however induction of regulatory t cells ( treg 's ) has become widely known as its central component .
the induction of foxp3 + treg cells requires cd103 + dendritic cells ( dcs ) .
herein , we will review the development / differentiation of mucosal resident dc subsets and their relative contribution to tolerance and immunity .
intestinal dcs are located throughout the villus lamina propria and in intestinal lymphoid tissue ( peyer 's patches , solitary isolated lymphoid tissue , and mesenteric ln ) , where they play a central role in sampling and processing luminal as well as peripheral self - antigen for presentation to t cells .
a seminal study by rescigno et al .   showed that cd11c+ cells send transepithelial dendrites from the lamina propria that penetrate through tight junctions and capture salmonella from the lumen .
lamina propria contains two major populations of cd11c+ mononuclear phagocytes : cd11ccd103+cd11b+cx3cr1 cells ( dcs ) and cd11ccd103cd11b+cx3cr1 + cells ( macrophages ) [ 6 , 9 , 1215 ] .
cx3cr1 + macrophages , rather than the cd103 + dcs , are sampling the intestinal luminal content by extending transepithelial dendrites [ 11 , 13 , 1618 ] .
dcs ( cd11c+cx3cr1 cells ) can be further subdivided into three major subsets based on the expression of cd11b and cd103 , with cd11b+cd103 + , cd11bcd103 + , and cd11bcd103 [ 19 , 20 ] ( figure 1 ) .
lymphoid tissue resident dcs include plasmacytoid dcs ( pdcs ) and cd8+ and cd11b+ conventional dcs ( cdcs )
. they can be found along the lymphoid organs associated with the intestine , including pps , isolated lymphoid follicles , and mlns .
nonlymphoid tissue dcs , found in the parenchyma of tissues , are also known as migratory dcs . under steady - state conditions ,
migratory dcs promote the expansion of regulatory t cells , required for tolerance to self - antigens [ 21 , 22 ] ( figure 1 ) .
on the other hand , during inflammatory response to infection , these cells promote protective t cell responses [ 23 , 24 ] .
the expression of the chemokine receptor ccr7 and its ligands ccl21 and ccl19 control whether migratory dcs move into draining lns . classic process of dc maturation occurs upon exposure to microbial stimuli or proinflammatory cytokines .
such modifications are essential for effective nave t cells priming and activation . on the other hand ,
migratory dc maturation is associated with tolerance induction rather than activation and proliferation , despite upregulation in mhc ii and cd40 .
induction of tolerance versus immunity by intestinal dc is , at least in part , mediated by retinoic acid receptors ( rar ) signaling [ 2629 ] .
thus , exposure to ra triggers expression of gut - homing receptors along with enhancing expansion of foxp3 + t cell and iga b cell differentiation . on the other hand ,
induction of gut - homing receptors on primed t cells as well as foxp3 + t cell differentiation in vitro is best achieved in the presence of migratory ( cd103+cd11b or cd11b+ ) dcs among other dc subsets [ 4 , 5 , 7 ] .
raldh2 is one of the enzymes that metabolize retinal to ra , cd103 + dcs express high levels of the gene encoding it  aldh1a2 .
small intestine - lamina propria and mln resident cd103 + dcs trigger rar signals and induce expression of ccr9 in responding t cells .
all dcs trigger limited rar signaling in t cells ; however high levels of ccr9 induction are a key function associated with small intestine - lamina propria and mln cd103 + dcs . on the other hand ,
the cd103+cd11b+ subset seems critical for the induction of proinflammatory th17 cells [ 19 , 20 ] given its high induction of il6 in response to microbial stimulation .
the interaction of fms - like tyrosine kinase 3 ( flt3 ) with its ligand ( flt3-l ) is critical for the generation of cd103 + dcs , both in mice and humans [ 37 , 38 ] .
pre - b cells as well as myeloid and monocytic lineages show upregulated flt3 mrna , while flt3-l mrna expression is ubiquitous .
treatment of mice with human flt3-l leads to activation of mouse flt3   triggering bone marrow hyperplasia along with hematopoietic stem and progenitor cell proliferation .
common dc progenitors are comprised within lineage ( lin)- negative , flt3-l+ cell subset [ 42 , 43 ] ( figure 1 ) .
pdcs and cdcs are both derived from the common dc precursor within this lin- flt3 + compartment [ 44 , 45 ] .
the transcription factor irf8 is required for development and activation of pdcs and cd8+ dcs [ 4648 ] and pu.1 is important for all conventional ( nonplasmacytoid ) dcs [ 49 , 50 ] .
intestinal cd103+cd11b dcs are developmentally related to the cd8+ lymphoid dc subset , since both subsets are dependent on the presence of the transcription factors irf8 , id2 , and batf3 .
most cd103 + small intestine - lamina propria dcs have been shown to develop directly from a circulating flt3 + common dc precursor and not from cd103 small intestine - lamina propria dcs   ( figure 1 ) .
interestingly , a great proportion of mln resident cd103 + dcs are thought to be derived from a migratory population arriving from small intestine - lamina propria that plays a critical role in presenting orally derived soluble antigen to t cells ( figure 1 ) .
presumably , these cells seize antigens locally in the small intestine and subsequently migrate into the mln .
cd103 mln dcs appear to be derived from a blood population that populate and expand the mln and is involved in the t cell priming to systemic antigens .
importantly , cd103 + dcs are present in normal and inflamed human mln and display similar phenotypic and functional properties to their murine counterparts .
ccr7 , a chemokine receptor which is required for dc migration from peripheral tissues into the draining ln , is required for accumulation of cd103 + dc in the mln , as ccr7-deficient hosts have reduced numbers of mln cd103 + dcs [ 5456 ] .
intestinal flora is composed of trillions of resident bacteria that can provide beneficial effects to the host . for example , bacterial metabolites including vitamins and short chain fatty acids are relevant for the host development , including lymphoid populations in the intestine . moreover ,
several host immune - regulatory mechanisms have evolved to prevent inappropriate activation of inflammatory responses in response to the commensal flora , including the hyporesponsiveness of intestinal epithelium and resident macrophages to bacterial toll - like receptor ligands [ 59 , 60 ] .
chemically induced and spontaneous colitis are reduced or abolished in antibiotic - treated mice and germ - free mice [ 6165 ] and bacteroides species and members of the enterobacteriaceae family including klebsiella pneumoniae and proteus mirabilis can promote colitis [ 66 , 67 ] .
inflammasome , a multiprotein complex that leads to caspase-1 initiated proteolytic processing of pro - interleukin-1 and pro - il18 into their active forms . in the intestine , salmonella triggers resident phagocytes to produce il-1 in an nlrc4-dependent manner leading to neutrophil recruitment .
the role of the nlrp3 inflammasome in intestinal inflammation is controversial . on one hand , mice lacking nlrp3 or caspase-1
were shown to be less susceptible to chemically induced colitis [ 71 , 72 ] .
on the other hand , it was shown that these same animals had increased susceptibility and worsened pathology [ 73 , 74 ] .
while il-1 blockage improves intestinal inflammation in different animal colitis models [ 75 , 76 ] , another study showed that genetic deficiency of il-1 leads to increased susceptibility to experimental colitis .
although it is not clear what the reasons for such differences in results are , one potential explanation is the composition of gut flora .
for instance , escherichia coli trigger nlrp3 inflammasome in bone marrow derived macrophages to produce il-1 [ 77 , 78 ] .
several commensal bacteroides and bifidobacteria strains can directly induce monocyte - derived dcs to acquire a tolerogenic phenotype . polysaccharide a from bacteroides fragilis , a gram - negative anaerobic commensal bacterium ,
can also associate with cd11c+ cells in mlns and drive a mixture of th1 systemic responses and il10-producing treg cells in the colonic lp .
these effects are associated with the modulation of apc function in the lamina propria [ 19 , 81 , 82 ] .
antigen presentation by cd103 + dcs can be tolerogenic [ 5 , 7 ] or immunogenic , dictated by the microenvironment [ 8385 ] .
those conditions should be crucial for the development of novel therapeutic approaches using cd103 + dcs in triggering mucosal immunity or tolerance . under steady - state conditions , lamina propria - resident cd103 + dcs are tolerogenic
for instance , mln cd103 + dcs purified from colitic mice triggered th1 responses along with high levels of il6 production [ 83 , 86 ] . during intestinal inflammation , mln cd103 + dc acquires these proinflammatory properties with no phenotypical and ontogenetic changes . naturally occurring cd4+cd25+foxp3
+ treg cells are thymus - derived and are important to modulate a wide range of immune - mediated pathologies , including autoimmunity , colitis , and chronic infection . however , inducible treg cells arising from the nave pool are particularly beneficial in the intestine .
the balance of triggering protective immunity to invading pathogens while retaining tolerance to dietary antigen and the commensal flora is critical .
these cells can be generated in the periphery from the naive t cell pool after , for example , the oral administration of antigen or the targeting of peptide ligands to dcs in vivo .
some specific nutrients are known to have notable effects on the modulation of mucosal immunity .
vitamin a , whose only source in mammals is through the diet , mediates several functions of cd103 + dcs .
its depletion from the diet inhibits treg differentiation induced by mln cd103 + dcs as well as inducing gut - homing receptors on t cells [ 88 , 89 ] .
tryptophan is another example of dietary element that is required for the ido - dependent tolerogenic effects of mucosal dcs   and for generation of ligands of the aryl hydrocarbon receptor ( ahr ) , such as l - kynurenine that regulates the balance between th17 and treg cell differentiation [ 9193 ] and has powerful direct anti - inflammatory activity on dcs .
diet - derived lipid mediators can activate anti - inflammatory peroxisome proliferator - activated receptor ( ppar) .
short chain fatty acids ( including acetate , butyrate , and propionate ) are among the most abundant metabolites derived from microbiota - mediated digestion of dietary fiber .
exposure of monocyte - derived dcs to butyrate and propionate prevented proinflammatory cytokine release induced after lps incubation .
in fact , animals deficient for butyrate receptor , gpr109a , are susceptible to the development of colitis and colon cancer .
exposure of curcumin triggers a tolerogenic activity in dcs , including upregulation of aldh1a2 and il10 while promoting foxp3 + treg cells .
the mucosal neural anatomy is disrupted in inflammatory bowel diseases ; intestine is permeated by a complex nervous system .
on the other hand , hematopoietic cells are responsive to neurotransmitters and mediators from the enteric nervous system exert immune - regulatory effects .
vasoactive intestinal peptide ( vip ) is produced by intestinal enteroendocrine and immune cells and has vasodilator and regulator of epithelial permeability activities .
vip suppresses lipopolysaccharide - induced dc maturation   while promoting differentiation of il10- and tgf--secreting treg cells [ 103105 ] . in agreement with these observations ,
taken together , these studies revised here point to the complexity of interactions between mucosal dcs , nonimmune cells , the microbiota , and ingested nutrients .
all these factors contribute to promoting and maintaining tolerance mediated by intestinal dcs under steady - state conditions .
while no single mediator plays a dominant role , redundancy among several pathways and components is evolutionary advantageous to ensure that homeostasis is maintained .
 dendritic cells present in the digestive tract are constantly exposed to environmental antigens , commensal flora , and invading pathogens . under steady - state conditions , 
 these cells have high tolerogenic potential , triggering differentiation of regulatory t cells to protect the host from unwanted proinflammatory immune responses to innocuous antigens or commensals . on the other hand 
 , these cells must discriminate between commensal flora and invading pathogens and mount powerful immune response against pathogens . 
 a potential result of unbalanced tolerogenic versus proinflammatory responses mediated by dendritic cells is associated with chronic inflammatory conditions , such as crohn 's disease , ulcerative colitis , food allergies , and celiac disease 
 . herein , we review the dendritic cell population involved in mediating tolerance and immunity in mucosal surfaces , the progress in unveiling their development in vivo , and factors that can influence their functions . 
1. Introduction
2. Subsets and Function
3. Mucosal Dendritic Cell Precursors and Homing Markers
4. Intestinal Mucosal Dendritic Cell Responses to Infection
5. Mucosal Tolerance and Dendritic Cells