Cytotoxic T-Cells from T-Cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and fas pathways
- Author(s)
- Dudek, NL; Thomas, HE; Mariana, L; Sutherland, RM; Allison, J; Estella, E; Angstetra, E; Trapani, JA; Santamaria, P; Lew, AM; Kay, TWH;
- Details
- Publication Year 2006-09,Volume 55,Issue #9,Page 2412-2418
- Journal Title
- DIABETES
- Publication Type
- Journal Article
- Abstract
- Cytotoxic T-cells are the major mediators of beta-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to beta-cell destruction using islet-specific CD8(+) T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for beta-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with beta-cells that do not respond to Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by overexpression of suppressor of cytokine signaling-1 (SOCS-1) in beta-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell-mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition.
- Publisher
- AMER DIABETES ASSOC
- Keywords
- NONOBESE DIABETIC MICE; TUMOR-NECROSIS-FACTOR; CYTOKINE SIGNALING-1; CLASS-I; ALPHA; DESTRUCTION; SUPPRESSOR; DEATH; OVEREXPRESSION; LYMPHOCYTES
- Publisher's Version
- https://doi.org/10.2337/db06-0109
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2006-09-01 12:00:00