In situ beta cell death promotes priming of diabetogenic CD8 T lymphocytes.
CTLs are important mediators of pancreatic beta cell destruction in the nonobese diabetic mouse model of type 1 diabetes. Cross-presentation of Ag is one means of priming CTLs. The death of Ag-bearing cells has been implicated in facilitating this mode of priming. The role of beta cell death in facilitating the onset of spontaneous autoimmune diabetes is unknown. Here, we used an adoptive transfer system to determine the time course of islet-derived Ag presentation to naive beta cell-specific CD8 T cells in nonobese diabetic mice and to test the hypothesis that beta cell death enhances the presentation of beta cell autoantigen. We have determined that beta cell death enhances autoantigen presentation. Priming of diabetogenic CD8 T cells in the pancreatic lymph nodes was negligible before 4 wk, progressively increased until 8 wk of age, and was not influenced by gender. Administration of multiple low doses of the beta cell toxin streptozotocin augmented in situ beta cell apoptosis and accelerated the onset and magnitude of autoantigen presentation to naive CD8 T cells. Increasing doses of streptozotocin resulted in both increased pancreatic beta cell death and significantly enhanced T cell priming. These results indicate that in situ beta cell death facilitates autoantigen-specific CD8 T cell priming and can contribute to both the initiation and the ongoing amplification of an autoimmune response.
Zhang
Yiqun
Y
Department of Medicine, British Columbia Research Institute of Children and Women's Health, University of British Columbia, Vancouver, British Columbia, Canada.
O'Brien
Bronwyn
B
Trudeau
Jacqueline
J
Tan
Rusung
R
Santamaria
Pere
P
Dutz
Jan P
JP
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D007274:Injections, Intraperitoneal; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013311:Streptozocin / Q000008:administration & dosage; D013997:Time Factors
D000276:Adjuvants, Immunologic; D001324:Autoantigens; D013311:Streptozocin