title: SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes.
abstract: CD8(+) cytotoxic T lymphocytes (CTL) can rapidly kill beta-cells and therefore contribute to the development of type 1 diabetes (T1D). CTL-mediated beta-cell killing can occur via perforin-mediated lysis, Fas-Fas-L interaction, and the secretion of TNF-alpha or IFN-gamma. The secretion of IFN-gamma can contribute to beta-cell death directly by eliciting nitric oxide production, and indirectly by upregulating MHC class I and 'unmasking' beta-cells for recognition by CTL. Earlier studies in the RIP-LCMV mouse model of diabetes showed that disruption of beta-cell IFN-gamma signaling alone abolished the direct detrimental effects of IFN-gamma, but not MHC class I upregulation. Suppressor of cytokine signaling-1 (SOCS-1) represses several crucial cytokine signaling pathways simultaneously, among them IFN-gamma and IL-1-beta. We therefore evaluated the protective capacity of islet cell SOCS-1 expression in the CD8(+) mediated RIP-LCMV diabetes model. Clinical disease was prevented in over 90% of the mice. Not only absence of MHC-I and Fas upregulation, but also resistance to cytokine-induced killing of beta-cells and a complete lack of CXCL-10 (IP10) production in islets led to a lack of islet infiltration and impaired activation of autoaggressive CD4(+) and CD8(+) T-cells in these mice. Thus, SOCS expression renders beta-cells resistant to CTL attack in a mouse model of T1D.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Barral
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Ling
authors.forename: Rima
authors.initials: R
authors.lastname: Darwiche
authors.forename: Evelyn
authors.initials: E
authors.lastname: Rodrigo
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
authors.forename: Mette
authors.initials: M
authors.lastname: Ejrnaes
authors.forename: Tom
authors.initials: T
authors.lastname: Wolfe
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000821:virology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D018121:Receptors, Cytokine / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis*; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D015395:Histocompatibility Antigens Class I; C104577:IP10-Mig receptor; D053583:Interleukin-1beta; D018121:Receptors, Cytokine; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019014:fas Receptor; D007371:Interferon-gamma; D053422:Receptor-Interacting Protein Serine-Threonine Kinases