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Release from Regulatory T Cell-Mediated Suppression during the Onset of Tissue-Specific Autoimmunity Is Associated with Elevated IL-21¹

Louise E. Clough^*, Chun Jing Wang^*, Emily M. Schmidt^*, George Booth, Tie Zheng Hou^*, Gemma A. Ryan^* and Lucy S. K. Walker^2,*

^* Medical Research Council Center for Immune Regulation, University of Birmingham Medical School, Birmingham; and Respiratory and Inflammation Research Area, AstraZeneca, Macclesfield, United Kingdom

The activity of regulatory T cells (Treg) is widely accepted to play a central role in preventing pathogenic immune responses against self-Ags. However, it is not clear why such regulation breaks down during the onset of autoimmunity. We have studied self-Ag-specific Treg during the induction of spontaneous diabetes. Our data reveal a shift in the balance between regulatory and pathogenic islet-reactive T cells in the pancreas-draining lymph nodes during disease onset. Treg function was not compromised during disease initiation, but instead conventional T cells showed reduced susceptibility to Treg-mediated suppression. Release from Treg suppression was associated with elevated levels of IL-21 in vivo, and provision of this cytokine abrogated Treg suppression in vitro and in vivo. These data suggest that immunological protection of a peripheral tissue by Treg can be subverted by IL-21, suggesting new strategies for intervention in autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Medical Research Council Career Development Fellowship (to L.S.K.W.). L.E.C. is funded by a Biotechnology and Biological Sciences Research Council/AstraZeneca Case Studentship.

² Address correspondence and reprint requests to Dr. Lucy Walker, Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Vincent Drive, Birmingham B15 2TT, U.K. E-mail address: L.S.Walker{at}bham.ac.uk

³ Abbreviations used in this paper: Treg, regulatory T cell; RIP, rat insulin promoter; Tconv, conventional T cell; mOVA, mouse OVA; LN, lymph node.