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International Immunology Advance Access originally published online on October 5, 2004
International Immunology 2004 16(11):1657-1662; doi:10.1093/intimm/dxh167
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© 2004 The Japanese Society for Immunology

Progression of spontaneous autoimmune diabetes is associated with a switch in the killing mechanism used by autoreactive CTL

Huilian Qin1, Jacqueline D. Trudeau1, Gregor S. D. Reid2, I-Fang Lee1, Jan P. Dutz3, Pere Santamaria4, C. Bruce Verchere1 and Rusung Tan1

1 Department of Pathology and Laboratory Medicine, 2 Department of Pediatrics and 3 Department of Medicine, University of British Columbia, BC's Children's Hospital, 4480 Oak Street, Vancouver, British Columbia, V6H 3V4, Canada
4 Department of Microbiology and Infectious Diseases and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada

Correspondence to: R. Tan; E-mail: roo{at}interchange.ubc.ca

Autoimmune (type 1) diabetes mellitus results from the destruction of insulin-producing pancreatic ß-cells by T lymphocytes. ß-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 ß-cell targets, transgenic ß-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.

Keywords: avidity maturation, CTL, Fas, non-obese diabetic, perforin

Transmitting editor: C. Terhorst


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