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Cytotoxic T-Cells From T-Cell Receptor Transgenic NOD8.3 Mice Destroy ß-Cells via the Perforin and Fas Pathways

¹ St. Vincent’s Institute, Fitzroy, Victoria, Australia
² Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
³ Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
⁴ Julia McFarlane Diabetes Research Center and Department of Microbiology and Infectious Disease, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada
⁵ The University of Melbourne Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia

Address correspondence and reprint requests to Professor Thomas W.H. Kay, St. Vincent’s Institute, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail: tkay{at}svi.edu.au

Abbreviations: CTL, cytotoxic T-cell; dn, dominant-negative; FasL, Fas ligand; FADD, Fas-associated death domain; IGRP, islet-specific glucose 6-phosphatase catalytic subunit–related protein; IFN, interferon; MHC, major histocompatibility complex; PLN, pancreatic lymph node; RIP, rat insulin promotor; SOCS-1, suppressor of cytokine signaling-1; TCR, T-cell receptor

Cytotoxic T-cells are the major mediators of ß-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to ß-cell destruction using islet-specific CD8⁺ T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for ß-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with ß-cells that do not respond to Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by overexpression of suppressor of cytokine signaling-1 (SOCS-1) in ß-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell–mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill ß-cells and the surprising blockade of NOD8.3 T-cell–mediated ß-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition.

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