antigen-presenting cells, principally dendritic cells, as well as other innate immune cells can provide various cytokines that induce the development of naive Cd4 T cells into distinct subsets. The environmental conditions, such as the exposure to various pathogens, determine which cytokines innate sensor cells will produce. Th1 cells differentiate in response to sequential IFn-γ and IL-12 signaling, whereas Th2 cells differentiate in response to IL-4. IL-6 produced by dendritic cells acts with transforming growth factor-β (TGF-β) to induce differentiation of Th17 cells, which upregulate expression of the IL-23 receptor and become responsive to IL-23. TFh cells also require IL-6 for their development, although it is not currently understood what additional signals might induce their differentiation from naive precursors. When pathogens are absent, the presence of TGF-β and IL-2, and the lack of IL-6, favor the development of induced T cells.
Fig. 9.32 Different members of the STAT family of transcription factors act immediately downstream of cytokines that determine CD4 T-cell subset development. With the exception of TGF-β, which participates in both Th17 and iTreg development, each of the cytokines that specify the development of distinct effector cells activates different members of the sTaT family of transcription factors. Th1 cell differentiation is dependent on sequential activation of sTaT1 and sTaT4 by binding of IFn-γ and IL-12 to their respective receptors on antigen-activated naive Cd4 T cells. Both of these sTaT factors participate in the induction of T-bet expression, which then cooperates with the sTaTs to program Th1 differentiation. Th2 cell differentiation is dependent on sTaT6 activation downstream of IL-4 receptor signaling. sTaT6 acts to increase GaTa3 expression, which cooperates with sTaT6 to program Th2 differentiation. IL-6 activates sTaT3, which, in concert with TGF-β, participates in the induction of rorγt expression and Th17 differentiation. IL-23, which acts later in Th17 differentiation, also activates sTaT3 to sustain and amplify the Th17 program. The programming of TFh cell differentiation by sTaT factors is not fully understood, although sTaT3 actions upstream of Bcl-6 expression are essential. activation of sTaT5 by IL-2 is important in iTreg differentiation and acts upstream of Foxp3 expression.
The activation of STAT1 by interferon induces in activated naive CD4 T cells induces the expression of another transcription factor, T-bet, which switches on the genes for IFN-γ and the inducible component of the IL-12 receptor, IL-12Rβ2 (the other component of the receptor, IL-12Rβ1, is already expressed on naive T cells). These T cells are now committed to becoming TH1 cells, and can be further activated by IL-12 produced by dendritic cells and macrophages to induce STAT4 signaling. STAT4 further upregulates T-bet expression and completes TH1 programming. Due to its central role in programming TH1 development, T-bet is sometimes referred to as a ‘master regulator’ of TH1 cell differentiation.