1. The Kimmel Center for Biology and Medicine of the Skirball Institute, and,
2. Howard Hughes Medical Institute, Departments of Microbiology and Pathology, New York University School of Medicine, New York, New York 10016, USA
3. Immunology Program Benaroya Research Institute Seattle, Washington 98101, USA
4. Department of Immunology University of Washington School of Medicine Seattle, and,
5. Howard Hughes Medical Institute, Department of Immunology, University of Washington Seattle, Washington 98195, USA

Correspondence to: Dan R. Littman^1,2 Correspondence and requests for materials should be addressed to D.R.L. (Email: littman@saturn.med.nyu.edu).

T helper cells that produce IL-17 (T_H17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T_H17 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, 2, 3, 4, 5}. Differentiation of both cell types requires transforming growth factor- (TGF-), but depends on distinct transcription factors: RORt (encoded by Rorc(t)) for T_H17 cells and Foxp3 for T_reg cells^{6, 7, 8}. How TGF- regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF- orchestrates T_H17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF- synergizes with interleukin (IL)-6 and IL-21 (refs 9–11) to promote IL-23 receptor (Il23r) expression, favouring T_H17 cell differentiation. High concentrations of TGF- repress IL23r expression and favour Foxp3⁺ T_reg cells. RORt and Foxp3 are co-expressed in naive CD4⁺ T cells exposed to TGF- and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF--induced Foxp3 inhibits RORt 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 RORt alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORt, thereby promoting T_H17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T_H17 or T_reg cells depends on the cytokine-regulated balance of RORt and Foxp3.

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