| First Author | Chong MM | Year | 2004 |
| Journal | J Immunol | Volume | 172 |
| Issue | 9 | Pages | 5714-21 |
| PubMed ID | 15100317 | Mgi Jnum | J:89692 |
| Mgi Id | MGI:3041064 | Doi | 10.4049/jimmunol.172.9.5714 |
| Citation | Chong MM, et al. (2004) Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction. J Immunol 172(9):5714-21 |
| abstractText | 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. |
