title: In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL-1 and IL-18.
abstract: CD4(+) T lymphocytes are required to induce spontaneous autoimmune diabetes in the NOD mouse. Since pancreatic β cells upregulate Fas expression upon exposure to pro-inflammatory cytokines, we studied whether the diabetogenic action of CD4(+) T lymphocytes depends on Fas expression on target cells. We assayed the diabetogenic capacity of NOD spleen CD4(+) T lymphocytes when adoptively transferred into a NOD mouse model combining: (i) Fas-deficiency, (ii) FasL-deficiency, and (iii) SCID mutation. We found that CD4(+) T lymphocytes require Fas expression in the recipients' target cells to induce diabetes. IL-1β has been described as a key cytokine involved in Fas upregulation on mouse β cells. We addressed whether CD4(+) T cells require IL-1β to induce diabetes. We also studied spontaneous diabetes onset in NOD/IL-1 converting enzyme-deficient mice, in NOD/IL-1β-deficient mice, and CD4(+) T-cell adoptively transferred diabetes into NOD/SCID IL-1β-deficient mice. Neither IL-1β nor IL-18 are required for either spontaneous or CD4(+) T-cell adoptively transferred diabetes. We conclude that CD4(+) T-cell-mediated β-cell damage in autoimmune diabetes depends on Fas expression, but not on IL-1β unveiling the existing redundancy regarding the cytokines involved in Fas upregulation on NOD β cells in vivo.
authors.affiliation: Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Green
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
authors.forename: Anaïs
authors.initials: A
authors.lastname: Panosa
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Eynon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Jovita A
authors.initials: JA
authors.lastname: Mezquita
authors.forename: Conchi
authors.initials: C
authors.lastname: Mora
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein / Q000172:deficiency / Q000378:metabolism; D005838:Genotype; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D020382:Interleukin-18; D053583:Interleukin-1beta; D019014:fas Receptor