TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function

T helper cells that produce IL- 17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T ( T-reg) cells control immune responses and inflammation triggered by the resident microflora(1-5). Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: ROR gamma t ( encoded by Rorc(gamma t)) for T(H)17 cells and Foxp3 for T-reg cells(6-8). How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro- inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-b synergizes with interleukin ( IL)- 6 and IL- 21 ( refs 9 - 11) to promote IL- 23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3(+) T-reg cells. ROR gamma t and Foxp3 are co- expressed in naive CD4(+) T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits ROR gamma t function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL- 17 ( also known as IL-17a) than those that express ROR gamma t alone. IL- 6, IL- 21 and IL- 23 relieve Foxp3- mediated inhibition of ROR gamma t, thereby promoting TH17 cell differentiation. Therefore, the decision of antigen- stimulated cells to differentiate into either T(H)17 or T-reg cells depends on the cytokine- regulated balance of ROR gamma t and Foxp3.