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ICOS Mediates the Development of Insulin-Dependent Diabetes Mellitus in Nonobese Diabetic Mice¹

Daniel Hawiger^*, Elise Tran^*, Wei Du, Carmen J. Booth, Li Wen, Chen Dong^¶ and Richard A. Flavell^2,*,

^* Department of Immunobiology and Howard Hughes Medical Institute, Department of Internal Medicine, Endocrinology, and Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510; and ^¶ Department of Immunology, M. D. Anderson Cancer Center, Houston, TX 77030

Initiation of diabetes in NOD mice can be mediated by the costimulatory signals received by T cells. The ICOS is found on Ag-experienced T cells where it acts as a potent regulator of T cell responses. To determine the function of ICOS in diabetes, we followed the course of autoimmune disease and examined T cells in ICOS-deficient NOD mice. The presence of ICOS was indispensable for the development of insulitis and hyperglycemia in NOD mice. In T cells, the deletion of ICOS resulted in a decreased production of the Th1 cytokine IFN-, whereas the numbers of regulatory T cells remained unchanged. We conclude that ICOS is critically important for the induction of the autoimmune process that leads to diabetes.

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 in part by the Diabetes Endocrinology Research Care Animal and Genetic Core (P30-DK-45735) and ADA Mentor-Based Postdoctoral Fellowship (R.A.F.). D.H. was supported by a National Multiple Sclerosis Society post-doctoral fellowship. R.A.F. is an investigator of the Howard Hughes Medical Institute.

² Address correspondence and reprint requests to Dr. Richard A. Flavell, Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, TAC S-569, New Haven, CT 06520. E-mail address: richard.flavell{at}yale.edu

³ Abbreviations used in this paper: EAE, experimental acute encephalomyelitis; Treg, regulatory T cell; T1DM, type 1 diabetes mellitus; GAD, glutamic acid decarboxylase.