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Polyclonal Adaptive Regulatory CD4 Cells That Can Reverse Type I Diabetes Become Oligoclonal Long-Term Protective Memory Cells¹

Elana Godebu^*,, Daphne Summers-Torres, Melissa M. Lin, Bas J. G. Baaten and Linda M. Bradley^2,

^* School of Medicine, University of California-San Diego, La Jolla, CA 92093; and Department of Immunology, Sidney Kimmel Cancer Center, San Diego, CA 92131

Type 1 diabetes is a CD4 cell-dependent disease that results from destruction of insulin-producing β cells in pancreatic islets. An ideal therapy would reverse diabetes shortly after onset when islet function in not yet fully ablated, and also prevent re-emergence of disease through the generation of memory cells that control the autoimmune response. In this study, we show that adaptive/induced polyclonal regulatory (TR) cells, which contain islet-reactive cells, fulfill these criteria in the NOD mouse model. CD4 cells induced to express FoxP3, IL-10, and TGF-β1 in response to TCR signaling and TGF-β1 can reverse diabetes with clinical restoration of prediabetic serum levels of IL-10. Unlike naturally occurring TR cells, these adaptive TR cells persist indefinitely (>1 year) as FoxP3⁺, CD25^– memory cells that self-renew. Establishment of memory is accompanied by narrowing of the T cell repertoire to usage of a single TCR β-chain, Vβ11, implying selection by Ag. With islet-specific adaptive TR cells, we show that memory is functionally stable and transferable. Therefore, adaptive TR cells, which can be readily generated from normal CD4 populations and become focused by Ag with induction of memory, may provide a treatment and a vaccine for the long-term cure of diabetes making them attractive as immunotherapeutic agents.

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 Juvenile Diabetes Research Foundation Grant JDRF 1-2006-174 and National Institutes of Health Grant R01 DK59438 (to L.M.B.).

² Address correspondence and reprint requests to Dr. Linda M. Bradley, Sidney Kimmel Cancer Center, 10905 Road to the Cure, San Diego, CA 92121. E-mail address: lbradley{at}skcc.org

³ Abbreviations used in this paper: TR, regulatory T cell; T1D, type 1 diabetes; LN, lymph node; PLN, peripheral LN; ICS, intracellular staining.

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