Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

Estelle Bettelli, Yijun Carrier, Wenda Gao, Thomas Korn, Terry B. Strom, Mohamed Oukka (), Howard L. Weiner and Vijay K. Kuchroo ()
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Estelle Bettelli: Center for Neurologic Diseases, Brigham and Women's Hospital
Yijun Carrier: Center for Neurologic Diseases, Brigham and Women's Hospital
Wenda Gao: Transplant Research Center, Beth Israel Hospital, Harvard Medical School
Thomas Korn: Center for Neurologic Diseases, Brigham and Women's Hospital
Terry B. Strom: Transplant Research Center, Beth Israel Hospital, Harvard Medical School
Mohamed Oukka: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School
Howard L. Weiner: Center for Neurologic Diseases, Brigham and Women's Hospital
Vijay K. Kuchroo: Center for Neurologic Diseases, Brigham and Women's Hospital

Nature, 2006, vol. 441, issue 7090, 235-238

Abstract: Abstract On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (TH) cells are traditionally thought to differentiate into TH1 and TH2 cell subsets. TH1 cells are necessary to clear intracellular pathogens and TH2 cells are important for clearing extracellular organisms1,2. Recently, a subset of interleukin (IL)-17-producing T (TH17) cells distinct from TH1 or TH2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury3,4,5. In contrast, CD4+CD25+Foxp3+ regulatory T (Treg) cells inhibit autoimmunity and protect against tissue injury6. Transforming growth factor-β (TGF-β) is a critical differentiation factor for the generation of Treg cells7. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation8,9, completely inhibits the generation of Foxp3+ Treg cells induced by TGF-β. We also demonstrate that IL-23 is not the differentiation factor for the generation of TH17 cells. Instead, IL-6 and TGF-β together induce the differentiation of pathogenic TH17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (TH17) T cells that induce autoimmunity and regulatory (Foxp3+) T cells that inhibit autoimmune tissue injury.

Date: 2006
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DOI: 10.1038/nature04753

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