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B7-Deficient Autoreactive T Cells Are Highly Susceptible to Suppression by CD4⁺CD25⁺ Regulatory T Cells¹

Kenneth F. May, Jr.^*, Xing Chang^*,, Huiming Zhang^*,, Kenneth D. Lute^*, Penghui Zhou, Ergun Kocak^*, Pan Zheng^*, and Yang Liu^2,*,

^* Department of Pathology, Divisions of Cancer Immunology and Dermatology, Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, OH 43210; and Department of Surgery, Division of Immunotherapy, Comprehensive Cancer Center and Program of Molecular Mechanism of Diseases, University of Michigan, Ann Arbor, MI 48109

CD4⁺CD25⁺ regulatory T cells (Tregs) suppress immunity to infections and tumors as well as autoimmunity and graft-vs-host disease. Since Tregs constitutively express CTLA-4 and activated T cells express B7-1 and B7-2, it has been suggested that the interaction between CTLA-4 on Tregs and B7-1/2 on the effector T cells may be required for immune suppression. In this study, we report that autopathogenic T cells from B7-deficient mice cause multiorgan inflammation when adoptively transferred into syngeneic RAG-1-deficient hosts. More importantly, this inflammation is suppressed by adoptive transfer of purified wild-type (WT) CD4⁺CD25⁺ T cells. WT Tregs also inhibited lymphoproliferation and acquisition of activation markers by the B7-deficient T cells. An in vitro suppressor assay revealed that WT and B7-deficient T cells are equally susceptible to WT Treg regulation. These results demonstrate that B7-deficient T cells are highly susceptible to immune suppression by WT Tregs and refute the hypothesis that B7-CTLA-4 interaction between effector T cells and Tregs plays an essential role in Treg function.

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 National Institutes of Health Grants AI51342 and CA12001 and a grant from the U.S. Army. K.F.M. was supported by the Ohio State University College of Medicine and Public Health Medical Scientist Program.

² Address correspondence and reprint requests to Dr. Yang Liu, Division of Immunotherapy, Department of Surgery, Comprehensive Cancer Center and Program of Molecular Mechanism of Diseases, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109. E-mail address: Yangl{at}umich.edu

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ regulatory T cell; DC, dendritic cell; RAG-1, recombinase-activating gene 1; WT, wild type.

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