In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL‐1 and IL‐18

• Published in: European journal of immunology 2011-05, Vol.41 (5), p.1344-1351
• Main Authors: Wen, Li, Green, Elizabeth A., Stratmann, Thomas, Panosa, Anaïs, Gomis, Ramon, Eynon, Elizabeth E., Flavell, Richard A., Mezquita, Jovita A., Mora, Conchi
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens; Autoimmune diabetes; Autoimmune diseases; b‐cell apoptosis; CD4+ T cells; CD4-Positive T-Lymphocytes - immunology; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Fas; Fas Ligand Protein - deficiency; Fas Ligand Protein - metabolism; fas Receptor - deficiency; fas Receptor - genetics; fas Receptor - metabolism; Genotype; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - pathology; Interleukin-18 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Lymphocytes; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Rodents
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201041216

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.