title: Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction.
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.
authors.affiliation: St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
authors.forename: Mark M W
authors.initials: MM
authors.lastname: Chong
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Rima
authors.initials: R
authors.lastname: Darwiche
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: Windy
authors.initials: W
authors.lastname: Irawaty
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.forename: Janette
authors.initials: J
authors.lastname: Allison
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007328:Insulin / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D019409:Interleukin-15 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019076:Transgenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma