1. Progression of spontaneous autoimmune diabetes is associated with a switch in the killing mechanism used by autoreactive CTL
- Author
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Huilian Qin, I-Fang Lee, Rusung Tan, C. Bruce Verchere, Gregor S. D. Reid, Jacqueline D. Trudeau, Pere Santamaria, and Jan P. Dutz
- Subjects
Cytotoxicity, Immunologic ,Aging ,Transgene ,Immunology ,Mice, Transgenic ,Disease ,Fas ligand ,Islets of Langerhans ,Mice ,Mice, Inbred NOD ,Diabetes mellitus ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,biology ,business.industry ,General Medicine ,medicine.disease ,Cytolysis ,CTL ,Diabetes Mellitus, Type 1 ,Granzyme ,Genes, T-Cell Receptor beta ,biology.protein ,business ,T-Lymphocytes, Cytotoxic - Abstract
Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic beta-cells by T lymphocytes. Beta-cell death that is induced by autoreactive CTL in diabetes involves both Fas/Fas ligand (FasL)- and perforin/granzyme-mediated pathways, although their relative contributions during the progression of the disease remain unknown. We demonstrate here that despite the preferential use of the Fas/FasL pathway for cytolysis of beta-cell targets, transgenic beta-cell-specific CTL were able to kill targets via the perforin pathway when triggered by a higher affinity stimulus. In addition, we show that the killing mechanism used by islet-associated CD8(+) T cells from non-obese diabetic mice changed as the mice aged and correspondingly, with the stage of diabetes. These results provide direct evidence for age-related changes in the cytotoxic pathways used by diabetogenic T cells during the progression of autoimmune diabetes.
- Published
- 2004