TH2 development requires IL-4. When an antigen-activated naive T cell encounters IL-4, its receptor activates STAT6, which promotes expression of the transcription factor GATA3. GATA3 is a powerful activator of the genes encoding several cytokines produced by TH2 cells, such as IL-4 and IL-13. GATA3 also induces its own expression, thereby stabilizing TH2 differentiation via cell-intrinsic positive feedback. The initial source of IL-4 that triggers a TH2 response has long been debated. Eosinophils, basophils, and mast cells are each attractive possibilities because they can produce abundant IL-4 when activated by chitin, a polysaccharide present in helminth parasites, as well as in insects and crustaceans, which induces TH2 responses. In mice treated with chitin, eosinophils and basophils are recruited into tissues and are activated to produce IL-4. In humans, group 2 ILCs can also produce IL-4, suggesting that these cells might contribute to TH2 differentiation, although this is unproven. Clearly, there are several innate immune cells that might contribute IL-4 for TH2 development, and the cellular source might differ, contingent on the inciting antigen. Similar to the positive feedback for TH1 cell development provided by IFN-γ produced by activated TH1 cells, IL-4 produced by activated TH2 cells may amplify TH2 development from naive T-cell precursors.
TH17 cells arise when the cytokines IL-6 and transforming growth factor (TGF)-β predominate during naive CD4 T-cell activation (see Figs. 9.31 and 9.32). Development of TH17 cells requires the actions of STAT3, which is activated by IL-6 signaling. Developing TH17 cells express the receptor for the cytokine IL-23, rather than the IL-12 receptor typical of TH1 cells, and the expansion and further development of TH17 effector activity seem to require IL-23, similar to the requirement for IL-12 in effective TH1 responses (see Figs.
9.31 and 9.32). The signature transcription factor, or master regulator, of TH17 cell differentiation is RORγt, a nuclear hormone receptor that is central to stabilizing the development of TH17 cells. The source of IL-6 and TGF-β required for TH17 cell differentiation is primarily derived from innate immune cells activated by microbial products. Unlike TH1 or TH2 cells, TH17 cells do not appear to directly induce further TH17 cell development from naive CD4 T cells via positive feedback, as they do not produce IL-6. However, IL-17 produced by TH17 cells appears to enhance IL-6 production by innate immune cells and provide an indirect mechanism for reinforcing TH17 differentiation from naive precursors.
upon antigen recognition in secondary lymphoid tissues, and not the thymus. They develop when naive T cells are activated in the presence of the cytokine transforming growth factor-β (TGF-β) and in the absence of IL-6 and other pro-inflammatory cytokines. Thus, it is the presence or absence of IL-6 that determines whether TGF-β co-signaling leads to the development of immunosuppressive Treg cells or of TH17 cells, which promote inflammation and the generation of immunity (Fig. 9.33). The generation of IL-6 by innate immune cells is regulated by the presence or absence of pathogens, with pathogen products tending to stimulate its production. In the absence of pathogens, IL-6 production is low, favoring differentiation of the immunosuppressive Treg cells and so preventing unwanted immune responses. Like nT cells, iT cells are distinguished by expression of the transcription factor FoxP3 and cell-surface CD25, and appear to be functionally equivalent to nT cells. Both iT and nT cells themselves can produce TGF-β, as well as IL-10, which act in an inhibitory manner to suppress immune responses and inflammation, and may act to support further iTreg differentiation.