Schematic representation of signaling and transcriptional regulation of Th17 polarization. Th17 cells are induced upon T-cell receptor activation in the presence of cytokines that activate Stat3, including IL-6, IL-21, and IL-23. IL-12 and IFN-γ, which signal via Stat4 and Stat1, respectively, promote type 1 differentiation and inhibit Th17 polarization. However, IL-23 also activates Stat4 (not shown), and it remains perplexing that animals deficient in Stat4 have impaired functionality of Th17 cells. Similarly, IL-4 signaling via Stat6 inhibits Th17 polarization and promotes type 2 differentiation. Phosphorylated Stat3 (pStat3) binds to the promoter regions and activates transcription of genes encoding master regulators of Th17 polarization: rorc (encoding Rorγt) and rora (encoding Rora) transcription factors. Batf and Irf4 form a functional complex that plays a central role in Rorγt-mediated activation of the type 17 molecular signature.⁴¹  Together with pStat3, Rorγt and Rorα activate the expression of genes encoding canonical Th17-associated cytokines IL-17A and IL-17F, as well as IL-21, IL-22, and others. IL-6–induced activation of Stat3 also augments the expression of the IL-23 receptor (IL-23R), thus increasing the sensitivity of early Th17 cells to the polarizing effects of IL-23. pStat3 also induces expression of Hif1α, which inhibits FoxP3 and promotes Th17 differentiation. IL-21 secreted by early Th17 cells acts in a self-amplified autocrine loop via the IL-21 receptor. IL-1 promotes Th17 polarization via activities of p38 mitogen-activated protein kinase (MAPK) and the Akt/mTOR pathway. IL-1 also induces Irf4, which directly augments IL-21 secretion. Th17 polarization is also increased by activation of aryl hydrocarbon receptors (Ahr). TGF-β1 signals via Smads that most likely limit expression of genes encoding T-bet, Gata3, and other Th1- and Th2-associated factors, thus increasing Th17 differentiation. TGF-β1 signaling in conjunction with retinoic acid (RA) and IL-2–induced pStat5 promotes FoxP3 expression and Treg differentiation. RA has been shown to either limit or (in lower concentrations) augment Th17 polarization. pStat5 directly inhibits pStat3 binding to IL-17 promoter (not shown). Both FoxP3 and Rorγt form complexes with Runx1 and reciprocally regulate each other.