TGF b induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORgt function
T helper cells that produce IL 17 (TH17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, TH17 cells are thought to protect the host from infection, whereas regulatory T (Treg) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor b (TGF b) but depends on distinct transcription factors: RORgt (encoded by Rorc(gt) for TH17 cells and Foxp3 for Treg cells. How TGF b regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro inflammatory cytokines, TGF b orchestrates TH17 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 TH17 cell differentiation. High concentrations of TGF b repress IL23r expression and favour Foxp3+ Treg cells. RORgt and Foxp3 are co expressed in naive CD4+ T cells exposed to TGF b and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF b induced Foxp3 inhibits RORgt 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 RORgt alone. IL 6, IL 21 and IL 23 relieve Foxp3 mediated inhibition of RORgt, thereby promoting TH17 cell differentiation. Therefore, the decision of antigen stimulated cells to differentiate into either TH17 or Treg cells depends on the cytokine regulated balance of RORgt and Foxp3.
Nature