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Protection from Type 1 Diabetes by Invariant NK T Cells Requires the Activity of CD4⁺CD25⁺ Regulatory T Cells¹

Dalam Ly^*,, Qing-Sheng Mi^2,*, Shabbir Hussain^* and Terry L. Delovitch^3,*,

^* Laboratory of Autoimmune Diabetes, Robarts Research Institute, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada

Invariant NK T (iNKT) cells regulate immune responses, express NK cell markers and an invariant TCR, and recognize lipid Ags in a CD1d-restricted manner. Previously, we reported that activation of iNKT cells by -galactosylceramide (-GalCer) protects against type 1 diabetes (T1D) in NOD mice via an IL-4-dependent mechanism. To further investigate how iNKT cells protect from T1D, we analyzed whether iNKT cells require the presence of another subset(s) of regulatory T cells (T_reg), such as CD4⁺CD25⁺ T_reg, for this protection. We found that CD4⁺CD25⁺ T cells from NOD.CD1d^–/– mice deficient in iNKT cell function similarly in vitro to CD4⁺CD25⁺ T cells from wild-type NOD mice and suppress the proliferation of NOD T responder cells upon -GalCer stimulation. Cotransfer of NOD diabetogenic T cells with CD4⁺CD25⁺ T_regs from NOD mice pretreated with -GalCer demonstrated that activated iNKT cells do not influence the ability of T_regs to inhibit the transfer of T1D. In contrast, protection from T1D mediated by transfer of activated iNKT cells requires the activity of CD4⁺CD25⁺ T cells, because splenocytes pretreated with -GalCer and then inactivated by anti-CD25 of CD25⁺ cells did not protect from T1D. Similarly, mice inactivated of CD4⁺CD25⁺ T cells before -GalCer treatment were also not protected from T1D. Our data suggest that CD4⁺CD25⁺ T cells retain their function during iNKT cell activation, and that the activity of CD4⁺CD25⁺ T_regs is required for iNKT cells to transfer protection from T1D.

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 grants from the Canadian Institutes of Health Research (MOP 64386) and Ontario Research and Development Challenge Fund (to T.L.D.). During these studies, T.L.D. was the Sheldon H. Weinstein Professor in Diabetes at the University of Western Ontario, D.L. was the recipient of a Canadian Diabetes Association Doctoral Student Award, and S.H. was the recipient of a Canadian Diabetes Association Postdoctoral Fellowship in honor of the late Flora I. Nichol.

² Current address: Center for Biotechnology and Genomic Medicine, Departments of Pathology and Medicine, Medical College of Georgia, Augusta, GA 30912-2400.

³ Address correspondence and reprint requests to Dr. Terry L. Delovitch, Laboratory of Autoimmune Diabetes, Robarts Research Institute, 100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail address: del{at}robarts.ca

⁴ Abbreviations used in this paper: T1D, type 1 diabetes; T_reg, regulatory T cell; T_resp, responder T cell; iNKT, invariant NK T cell; DC, dendritic cell; -GalCer, -galactosylceramide; PLN, pancreatic draining lymph node; MFI, mean fluorescent intensity.

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