(also known as type 1 and type 2 helper t cells, respectively). th1 helper cells lead to an increased cell-mediated response (primarily by macrophages and cytotoxic t cells), typically against intracellular bacteria and protozoa. they are triggered by the polarising cytokine il-12 and their effector cytokines are ifn-γ and il-2. the main effector cells of th1 immunity are macrophages as well as cd8 t cells, igg b cells, and ifn-γ cd4 t cells. the key th1 transcription factors are stat4 and t-bet. ifn-γ secreted by cd4 t cells can activate macrophages to phagocytose and digest intracellular bacteria and protozoa. in addition, ifn-γ can activate inos (inducible nitric oxide synthase) to produce nitric oxide free radicals to directly kill intracellular bacteria and protozoa. th1 overactivation against autoantigens will cause type iv or delayed-type hypersensitivity reaction. tuberculin reaction and type 1 diabetes belong to this category of autoimmunity. th2 helper cells lead to a humoral immune response, typically against extracellular parasites such as helminths. they are triggered by the polarising cytokines il-4 and il-2, and their effector cytokines are il-4, il-5, il-9, il-10, il-13 and il-25. the main effector cells are eosinophils, basophils, and mast cells as well as b cells, and il-4/il-5 cd4 t cells. the key th2 transcription factors are stat6 and gata3. il-4 is the positive feedback cytokine for th2 cells differentiation. besides, il-4 stimulates b-cells to produce ige antibodies, which in turn stimulate mast cells to release histamine, serotonin, and leukotriene to cause broncho-constriction, intestinal peristalsis, gastric fluid acidification to expel helminths. il-5 from cd4 t cells will activate eosinophils to attack helminths. il-10 suppresses th1 cells differentiation and function of dendritic cells. th2 overactivation against antigen will cause type i hypersensitivity which is an allergic reaction mediated by ige. allergic rhinitis, atopic dermatitis, and asthma belong to this category of overactivation . in addition to expressing different cytokines, th2 cells also differ from th1 cells in their cell surface glycans (oligosaccharides), which makes them less susceptible to some inducers of cell death. th1/th2 model for helper t cells. an antigen is ingested and processed by an apc. it presents fragments from it to t cells. the upper, th0, is a t helper cell. the fragment is presented to it by mhc2. ifn-γ, interferon γ; tgf-β, transforming growth factor β; mø, macrophage; il-2, interleukin 2; il-4, interleukin 4 th1/th2 dichotomy type 1/ th1type 2/ th2 main partner cell typemacrophage, cd8+ t cellb-cell, eosinophil, mast cell cytokines producedinterferon gamma (ifnγ) and tnf-β. interleukin 2 and interleukin 10 production has been reported in activated th1 cell. interleukin 4, interleukin 5, interleukin 6, interleukin 9, interleukin 10, interleukin 13 immune stimulation promotedcellular immune system. maximizes the killing efficacy of the macrophages and the proliferation of cytotoxic cd8+ t cells. also promotes the production of igg, an opsonizing antibody. humoral immune system. stimulates b-cells into proliferation, to induce b-cell antibody class switching, and to increase neutralizing antibody production (igg, igm and iga as well as ige antibodies). other functionsthe type 1 cytokine ifnγ increases the production of interleukin 12 by dendritic cells and macrophages, and via positive feedback, il-12 stimulates the production of ifnγ in helper t cells, thereby promoting the th1 profile. ifnγ also inhibits the production of cytokines such as interleukin 4, an important cytokine associated with the type 2 response, and thus it also acts to preserve its own response. the type 2 response promotes its own profile using two different cytokines. interleukin 4 acts on helper t cells to promote the production of th2 cytokines (including itself; it is auto-regulatory), while interleukin 10 (il-10) inhibits a variety of cytokines including interleukin 2 and ifnγ in helper t cells and il-12 in dendritic cells and macrophages. the combined action of these two cytokines suggests that once the t cell has decided to produce these cytokines, that decision is preserved (and also encourages other t cells to do the same). while we know about the types of cytokine patterns helper t cells tend to produce, we understand less about how the patterns themselves are decided. various evidence suggests that the type of apc presenting the antigen to the t cell has a major influence on its profile. other evidence suggests that the concentration of antigen presented to the t cell during primary activation influences its choice. the presence of some cytokines (such as the ones mentioned above) will also influence the response that will eventually be generated, but our understanding is nowhere near complete. th17 helper cells main article: t helper 17 cell th17 helper cells are a subset of t helper cells developmentally distinct from th1 and th2 lineages producing interleukin 17 (il-17). th cells produce il-17 which is a pro inflammatory substance. this means it is especially good at fighting extracellular pathogens and fungi. thαβ helper cells thαβ helper cells provide the host immunity against viruses. their differentiation is triggered by ifn α/β or il-10. their key effector cytokine is il-10. their main effector cells are nk cells as well as cd8 t cells, igg b cells, and il-10 cd4 t cells. the key thαβ transcription factors are stat1 and stat3 as well as irfs. il-10 from cd4 t cells activate nk cells' adcc to apoptose virus-infected cells and to induce host as well as viral dna fragmentation. ifn alpha/beta can suppress transcription to avoid virus replication and transmission. overactivation of thαβ against autoantigen will cause type 2 antibody-dependent cytotoxic hypersensitivity. myasthenia gravis or graves' disease belong to this category. limitations to the th1/th2 model the interactions between cytokines from the th1/th2 model can be more complicated in some animals. for example, the th2 cytokine il-10 inhibits cytokine production of both th subsets in humans. human il-10 (hil-10) suppresses the proliferation and cytokine production of all t cells and the activity of macrophages, but continues to stimulate plasma cells, ensuring that antibody production still occurs. as such, hil-10 is not believed to truly promote the th2 response in humans, but acts to prevent over-stimulation of helper t cells while still maximising the production of antibodies. there are also other types of t cells that can influence the expression and activation of helper t cells, such as natural regulatory t cells, along with less common cytokine profiles such as the th3 subset of helper t cells. terms such as "regulatory" and "suppression" have become ambiguous after the discovery that helper cd4+ t cells are also capable of regulating (and suppressing) their own responses outside of dedicated regulatory t cells. one major difference between regulatory t cells and effector t cells is that regulatory t cells typically serve to modulate and deactivate the immune response, while effector t cell groups usually begin with immune-promoting cytokines and then switch to inhibitory cytokines later in their life cycle. the latter is a feature of th3 cells, which transform into a regulatory subset after its initial activation and cytokine production. both regulatory t cells and th3 cells produce the cytokine transforming growth factor-beta (tgf-β) and il-10. both cytokines are inhibitory to helper t cells; tgf-β suppresses the activity of most of the immune system. there is evidence to suggest that tgf-β may not suppress activated th2 cells as effectively as it might suppress naive cells, but it is not typically considered a th2 cytokine. the novel characterisation of another t helper subtype, t helper 17 cells (th17) has cast further doubt on the basic th1/th2 model. these il-17 producing cells were initially described as a pathogenic population implicated in autoimmunity but are now thought to have their own distinct effector and regulatory functions. of note, some evidence suggest that functional plasticity is an intrinsic capacity of t helper cells. indeed, a study in mice demonstrated that th17 cells transform into th1 cells in vivo. a subsequent study furthermore showed that extensive t helper cell plasticity is also prominent in man. many of the cytokines in this article are also expressed by other immune cells (see individual cytokines for details), and it is becoming clear that while the original th1/th2 model is enlightening and gives insight into the functions of helper t cells, it is far too simple to define its entire role or actions. some immunologists question the model completely, as some in vivo studies suggest that individual helper t cells usually do not match the specific cytokine profiles of the th model, and many cells express cytokines from both profiles. that said, the th model has still played an important part in developing our understanding of the roles and behaviour of helper t cells and the cytokines they produce during an immune response. studies by stockinger et al. revealed that another t helper subset may exist. th9 cells are claimed to be an il9 (interleukin 9)–producing t cell subset focused on defending helminth infections. memory t cell main article: memory t cell historically, memory t cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers. central memory t cells reside in the lymph nodes while effector memory t cells lack the c-c chemokine receptor type 7 (ccr7) and l-selectin (cd62l) receptors, which prevents them from trafficking to the lymph nodes. additional populations of memory t cells are now known to exist. these include tissue-resident memory t (trm) cells and virtual memory t cells. the single unifying theme for all memory t cell subtypes is that they are long-lived and can expand quickly to large numbers of effector t cells upon encountering their cognate antigen. by this mechanism they provide the immune system with "memory" against previously encountered pathogens. role in disease considering the diverse and important role helper t cells play in the immune system, it is not surprising that these cells often influence the immune response against disease. they also occasionally generate non-beneficial responses. very rarely, the helper t cell response could lead to the death of the host. antitumor immunity main article: cd4+ t cells and antitumor immunity hypersensitivity the immune system must achieve a balance of sensitivity in order to respond to foreign antigens without responding to the antigens of the host itself. when the immune system responds to very low levels of antigen that it usually shouldn't respond to, a hypersensitivity response occurs. hypersensitivity is believed to be the cause of allergy and some auto-immune disease. hypersensitivity reactions can be divided into four types: type 1 hypersensitivity includes common immune disorders such as asthma, allergic rhinitis (hay fever), eczema, urticaria (hives) and anaphylaxis. these reactions all involve ige antibodies, which require a th2 response during helper t cell development. preventive treatments, such as corticosteroids and montelukast, focus on suppressing mast cells or other allergic cells; t cells do not play a primary role during the actual inflammatory response. it's important to note that the numeral allocation of hypersensitivity "types" does not correlate (and is completely unrelated) to the "response" in the th model. type 2 and type 3 hypersensitivity both involve complications from auto-immune or low affinity antibodies. in both of these reactions, t cells may play an accomplice role in generating these auto-specific antibodies, although some of these reactions under type 2 hypersensitivity would be considered normal in a healthy immune system (for example, rhesus factor reactions during child-birth is a normal immune response against child antigens). the understanding of the role of helper t cells in these responses is limited but it is generally thought that th2 cytokines would promote such disorders. for example, studies have suggested that lupus (sle) and other auto-immune diseases of similar nature can be linked to the production of th2 cytokines. type 4 hypersensitivity, also known as delayed type hypersensitivity, are caused via the over-stimulation of immune cells, commonly lymphocytes and macrophages, resulting in chronic inflammation and cytokine release. antibodies do not play a direct role in this allergy type. t cells play an important role in this hypersensitivity, as they activate against the stimulus itself and promote the activation of other cells; particularly macrophages via th1 cytokines. other cellular hypersensitivities include cytotoxic t cell mediated auto-immune disease, and a similar phenomenon; transplant rejection. helper t cells are required to fuel the development of these diseases. in order to create sufficient auto-reactive killer t cells, interleukin-2 must be produced, and this is supplied by cd4+ t