1. Center for Neurologic Diseases, Brigham and Women's Hospital, and
2. Transplant Research Center, Beth Israel Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
4. *These authors contributed equally to this work

Correspondence to: Mohamed Oukka³Vijay K. Kuchroo¹ Correspondence and requests for materials should be addressed to V.K.K. (Email: vkuchroo@rics.bwh.harvard.edu) and M.O. (Email: moukka@rics.bwh.harvard.edu).

Abstract

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T_H) cells are traditionally thought to differentiate into T_H1 and T_H2 cell subsets. T_H1 cells are necessary to clear intracellular pathogens and T_H2 cells are important for clearing extracellular organisms^{1, 2}. Recently, a subset of interleukin (IL)-17-producing T (T_H17) cells distinct from T_H1 or T_H2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury^{3, 4, 5}. In contrast, CD4⁺CD25⁺Foxp3⁺ regulatory T (T_reg) cells inhibit autoimmunity and protect against tissue injury⁶. Transforming growth factor- (TGF-) is a critical differentiation factor for the generation of T_reg cells⁷. Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation^{8, 9}, completely inhibits the generation of Foxp3⁺ T_reg cells induced by TGF-. We also demonstrate that IL-23 is not the differentiation factor for the generation of T_H17 cells. Instead, IL-6 and TGF- together induce the differentiation of pathogenic T_H17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T_H17) T cells that induce autoimmunity and regulatory (Foxp3⁺) T cells that inhibit autoimmune tissue injury.

1. Center for Neurologic Diseases, Brigham and Women's Hospital, and
2. Transplant Research Center, Beth Israel Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
3. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
4. *These authors contributed equally to this work

Correspondence to: Mohamed Oukka³Vijay K. Kuchroo¹ Correspondence and requests for materials should be addressed to V.K.K. (Email: vkuchroo@rics.bwh.harvard.edu) and M.O. (Email: moukka@rics.bwh.harvard.edu).

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