RORγt and Foxp3 are central factors in Th17 and Treg cell differentiation, respectively. Th17 inducing cytokines (in green) induce RORγt through STAT3 (IL-6, IL-21, and IL-23) and IRF4 (induced by TCR activation). However, none of the RORγt-inducing cytokines can induce Th17 differentiation in the absence of TGF-β signaling. Th17 suppressing cytokines (in red) act in several ways. IL-2 acts through STAT5, and IL-27 possibly through SOCS3 and STAT3, inhibiting RORγt-upregulation. Retinoic acid (RA), which promotes Treg development, and TGF-β by itself, which induces Foxp3 expression, decrease Th17 differentiation. In addition, Th1 and Th2 inducing cytokines, such as IL-4, IFNγ, and IL-25 also inhibit Th17 differentiation by unknown mechanisms. TGF-β thus plays a dual role by being absolutely required for Th17 cell differentiation and by also promoting Treg cell development.