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. 2015 Jun 17;6:322. doi: 10.3389/fimmu.2015.00322

Figure 2.

Figure 2

CD4+ T-cell differentiation. Naïve CD4+ T cells can differentiate into different T helper cell subsets. In MS, Th1 and Th17 cells are regarded to be disease-promoting, whereas regulatory T cells and Th2 cells seem to exert a protective effect. The exact role of Th9 and Th22 cells remains to be further clarified. Th1 cells, which predominantly produce TNF (95), IFN-γ, IL-2 (332), and lymphotoxin-α (333), are induced by IL-12 (95). Their master regulator is the transcription factor (TF) T-bet (334). They mainly interact with cytotoxic CD8+ T cells and macrophages (335). Th2 cells, which mainly interact with B cells (335), are induced by IL-4 and secrete IL-4, IL-5, IL-6, and IL-10 (101, 333, 335). GATA-3 is the most important TF of Th2 cells (336). IL-6, TGF-β (93), and IL-23 (95) are important cytokines for the induction of Th17 cells producing IL-17, IL-6, TNFα (95), IL-21 (94), IL-22 (337). RORγt is the master regulator of this T-cell subset (338). Interestingly, TGF-β is also necessary for the induction of regulatory T cells, whereas IL-6 must be absent in this case (93, 117). The master regulator for the induction of regulatory T cells is the TF Foxp3 (52, 339). Regulatory T cells then produce TGF-β and IL-10 (117). Recently also Th9 cells and Th22 have been identified to be a discrete T-cell subset. The induction of Th9 cells is promoted by IL-4 and TGF-β (340). Th9 cells produce IL-9 and to a lesser extent IL-10 (340, 341). Under the influence of TGF-β, Th2 cells can switch their phenotype and become Th9 cells (342). Master regulators for Th9 and Th22 cells have not been identified so far. Important factors for the induction of Th9 cells are PU.1, IRF, BATF, different STAT factors, and TGF-β-induced SMADS (341, 343). Priming of IL-22 producing Th22 cells is promoted by IL-6 and TNF (103). The transcription factor aryl hydrocarbon regulator (AHR) seems to exert an important influence on IL-22 production (344).