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

• Published in: Nature (London) Vol. 453; no. 7192; pp. 236 - 240
• Main Authors: Zhou, Liang, Lopes, Jared E., Chong, Mark M. W., Ivanov, Ivaylo I., Min, Roy, Victora, Gabriel D., Shen, Yuelei, Du, Jianguang, Rubtsov, Yuri P., Rudensky, Alexander Y., Ziegler, Steven F., Littman, Dan R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2008; Nature Publishing
• Subjects: Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Fundamental and applied biological sciences. Psychology; Humanities and Social Sciences; letter; Molecular and cellular biology; multidisciplinary; Science; Science (multidisciplinary); Foxp3 transcription factor; TH17 lymphocyte; Inhibition; Cell differentiation; Transforming growth factor β
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature06878

The cytokine TFG-β contributes to the differentiation of both regulatory T cells and T H 17 cells. This paper shows that in intestinal lamina propria cell lineage differentiation depends on the local TFG-β concentration. 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 , 2 , 3 , 4 , 5 . Differentiation of both cell types requires transforming growth factor-β (TGF-β), but depends on distinct transcription factors: RORγt (encoded by Rorc(γt) ) for T H 17 cells and Foxp3 for T reg cells 6 , 7 , 8 . How TGF-β regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-β orchestrates T H 17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-β 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-β repress IL23r expression and favour Foxp3 + T reg cells. RORγt and Foxp3 are co-expressed in naive CD4 + T cells exposed to TGF-β and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro , TGF-β-induced Foxp3 inhibits RORγt 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 RORγt alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORγt, thereby promoting T H 17 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 RORγt and Foxp3.