Progression of spontaneous autoimmune diabetes is associated with a switch in the killing mechanism used by autoreactive CTL.
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.
Department of Pathology and Laboratory Medicine, University of British Columbia, BC's Children's Hospital, 4480 Oak Street, Vancouver, British Columbia, V6H 3VA, Canada.
Huilian
H
Qin
Jacqueline D
JD
Trudeau
Gregor S D
GS
Reid
I-Fang
IF
Lee
Jan P
JP
Dutz
Pere
P
Santamaria
C Bruce
CB
Verchere
Rusung
R
Tan
D000375:Aging / Q000276:immunology* / Q000473:pathology; D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000235:genetics / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019674:Genes, T-Cell Receptor beta / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology