1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 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 M.O. (Email: moukka@rics.bwh.harvard.edu) or V.K.K. (Email: vkuchroo@rics.bwh.harvard.edu).

Abstract

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions¹. Recently a subset of T cells, distinct from T helper (T_H)1 and T_H2 cells, producing interleukin (IL)-17 (T_H17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation^{2, 3, 4, 5}. We and others have shown that transforming growth factor (TGF)- and IL-6 together induce the differentiation of T_H17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3⁺ regulatory T cells (T_reg cells) or T_H17 cells^{6, 7, 8, 9}. Whereas TGF- induces Foxp3 and generates T_reg cells, IL-6 inhibits the generation of T_reg cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T_H17 and T_reg cells. Here we show that IL-6-deficient (Il6^-/-) mice do not develop a T_H17 response and their peripheral repertoire is dominated by Foxp3⁺ T_reg cells. However, deletion of T_reg cells leads to the reappearance of T_H17 cells in Il6^-/- mice, suggesting an additional pathway by which T_H17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF- to induce T_H17 cells in naive Il6^-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T_H17 response.

1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
2. Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 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 M.O. (Email: moukka@rics.bwh.harvard.edu) or V.K.K. (Email: vkuchroo@rics.bwh.harvard.edu).

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