The Journal of Experimental Medicine
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Published 21 June 2004. doi:10.1084/jem.20040124
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 12, 1725-1730
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Brief Definitive Report

 Cooperative Roles of CTLA-4 and Regulatory T Cells in Tolerance to an Islet Cell Antigen

Mark P. Eggena, Lucy S.K. Walker, Vijaya Nagabhushanam, Luke Barron, Anna Chodos, and Abul K. Abbas

Department of Pathology, University of California, San Francisco, CA 94143

Address correspondence to Abul K. Abbas, Dept. of Pathology, UCSF, M590, 505 Parnassus Ave., San Francisco, CA 94143. Phone: (415) 514-0681; Fax: (415) 502-4563; email: aabbas{at}itsa.ucsf.edu

Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag–/– background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag–/– T cells, which are all CD25–, are transferred into islet antigen–expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4–/–/Rag–/– OVA-specific T cells (also CD25–) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen.

Key Words: autoimmunity • tolerance • diabetes • T cell activation • interferon gamma

M.P. Eggena, L.S.K. Walker, and V. Nagabhushanam contributed equally to the work.

L.S.K. Walker's present address is MRC Centre for Immune Regulation, University of Birmingham Medical School, Vincent Drive, Birmingham B15 2TT, England, UK.

Abbreviations used in this paper: RIP, rat insulin promoter; Treg cell, regulatory T cell.


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