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CD4⁺CD25⁺ Regulatory T-Cells Inhibit the Islet Innate Immune Response and Promote Islet Engraftment

¹ Department of Gene and Cell Medicine, and Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, New York
² Institute for Cancer Genetics, Columbia University, New York, New York
³ Division of Nephrology, Mount Sinai School of Medicine, New York, New York
⁴ Department of Surgery, Columbia University, New York, New York
⁵ Center for Immunobiology, Mount Sinai School of Medicine, New York, New York

Address correspondence and reprint requests to Dr. Jonathan S. Bromberg, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1104, New York, NY 10029-6574. E-mail: jon.bromberg{at}mountsinai.org

Abbreviations: IFN, interferon; IL, interleukin; mAb, monoclonal antibody; PE, phycoethrin; TGF, transforming growth factor; TNF-, tumor necrosis factor-

Early islet cell loss is a significant problem in clinical islet cell transplantation. Diverse stress stimuli induce innate immune responses in islets that contribute to ß-cell dysfunction, inflammation, and loss. Here, we show that cytokine-stimulated murine islets express multiple inflammatory chemokines that recruit T-cells and thereby impair islet function in vitro and in vivo. Both nonislet ductal and exocrine elements and the individual islet cellular components contribute to this innate immune response. CD4⁺CD25⁺ regulatory T-cells inhibit islet chemokine expression through a cell contact–dependent, soluble factor–independent mechanism and inhibit effector T-cell migration to the islet. Regulatory T-cells can also migrate to stimulated islets. Cotransfer of regulatory T-cells with islets in a transplantation model prevents islet innate immune responses and inflammation and preserves normal architecture and engraftment. Regulatory T-cell inhibition of multiple components of innate immune responses may be a fundamental aspect of their function that influences ischemia-reperfusion injury and adaptive immunity.

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