Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8(+) T cell-mediated autoimmune destruction
- Author(s)
- Chong, MMW; Chen, Y; Darwiche, R; Dudek, NL; Irawaty, W; Santamaria, P; Allison, J; Kay, TWH; Thomas, HE;
- Details
- Publication Year 2004-05-01,Volume 172,Issue #9,Page 5714-5721
- Journal Title
- JOURNAL OF IMMUNOLOGY
- Publication Type
- Journal Article
- Abstract
- In type 1 diabetes, cytokine action on beta cells potentially contributes to beta cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block beta 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-gamma-induced Fas expression on beta cells. Fas expression was up-regulated on beta cells in vivo in prediabetic NOD8.3 mice, and this was inhibited by SOCS-1. Additionally, IFN-gamma-induced class I MHC up-regulation and TNF- and IFN-gamma-induced IL-15 expression by beta 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 beta cell responses to cytokines impairs recognition by CD8(+) T cells and blocks multiple mechanisms of beta 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.
- Publisher
- AMER ASSOC IMMUNOLOGISTS
- Keywords
- NONOBESE DIABETIC MICE; TUMOR-NECROSIS-FACTOR; IFN-GAMMA; NOD MICE; EXPRESSION; FAS; LYMPHOCYTES; MOUSE; PERFORIN; INTERLEUKIN-15
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- Refer to copyright notice on published article.
Creation Date: 2004-05-01 12:00:00