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CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity¹

Emily M. Schmidt^2,*, Chun Jing Wang^2,*, Gemma A. Ryan^*, Louise E. Clough^*, Omar S. Qureshi^*, Margaret Goodall^*, Abul K. Abbas, Arlene H. Sharpe, David M. Sansom^* and Lucy S. K. Walker^3,*

^* Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom; Department of Pathology, University of California, San Francisco, CA 94143; and Department of Pathology, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115

The CTLA-4 pathway is recognized as a major immune inhibitory axis and is a key therapeutic target for augmenting antitumor immunity or curbing autoimmunity. CTLA-4-deficient mice provide the archetypal example of dysregulated immune homeostasis, developing lethal lymphoproliferation with multiorgan inflammation. In this study, we show that surprisingly these mice have an enlarged population of Foxp3⁺ regulatory T cells (Treg). The increase in Treg is associated with normal thymic output but enhanced proliferation of Foxp3⁺ cells in the periphery. We confirmed the effect of CTLA-4 deficiency on the Treg population using OVA-specific Treg which develop normally in the absence of CTLA-4, but show increased proliferation in response to peripheral self-Ag. Functional analysis revealed that Ag-specific Treg lacking CTLA-4 were unable to regulate disease in an adoptive transfer model of diabetes. Collectively, these data suggest that the proliferation of Treg in the periphery is tuned by CTLA-4 signals and that Treg expression of CTLA-4 is required for regulation of pancreas 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., holds a Biotechnology and Biological Sciences Research Council/Astrazeneca Case Studentship and E.M.S. and G.A.R. are supported by the University of Birmingham Scientific Projects Committee.

² E.M.S. and C.J.W. contributed equally to the work.

³ Address correspondence and reprint requests to Dr. Lucy S. K. Walker, Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, B15 2TT, U.K. E-mail address: L.S.Walker{at}bham.ac.uk

⁴ Abbreviations used in this paper: Treg, regulatory T cell; RIP, rat insulin promoter; LN, lymph node; DC, dendritic cell; mOVA, membrane OVA.

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