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Suppressor of Cytokine Signaling-1 Overexpression Protects Pancreatic Cells from CD8⁺ T Cell-Mediated Autoimmune Destruction¹

Mark M. W. Chong^*,, Ye Chen, Rima Darwiche^*, Nadine L. Dudek^*, Windy Irawaty, Pere Santamaria, Janette Allison, Thomas W. H. Kay^2,* and Helen E. Thomas^*

^* St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Center, University of Calgary, Alberta, Canada; and Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia

In type 1 diabetes, cytokine action on cells potentially contributes to cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block cell responsiveness to multiple cytokines, we overexpressed suppressor of cytokine signaling-1 (SOCS-1). This completely prevented progression to diabetes in CD8⁺ TCR transgenic nonobese diabetic (NOD) 8.3 mice without affecting pancreas infiltration and partially prevented diabetes in nontransgenic NOD mice. SOCS-1 appeared to protect at least in part by inhibiting TNF- and IFN--induced Fas expression on cells. Fas expression was up-regulated on cells in vivo in prediabetic NOD8.3 mice, and this was inhibited by SOCS-1. Additionally, IFN--induced class I MHC up-regulation and TNF- and IFN--induced IL-15 expression by cells were inhibited by SOCS-1, which correlated with suppressed 8.3 T cell proliferation in vitro. Despite this, 8.3 T cell priming in vivo appeared unaffected. Therefore, blocking cell responses to cytokines impairs recognition by CD8⁺ T cells and blocks multiple mechanisms of cell destruction, but does not prevent T cell priming and recruitment to the islets. Our findings suggest that increasing SOCS-1 expression may be useful as a strategy to block CD8⁺ T cell-mediated type 1 diabetes as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.

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