Beta cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice.
Type 1 diabetes (T1D) is caused by the destruction of insulin-producing islet beta cells. CD8 T cells are prevalent in the islets of T1D patients and are the major effectors of beta cell destruction in nonobese diabetic (NOD) mice. In addition to their critical involvement in the late stages of diabetes, CD8 T cells are implicated in the initiation of disease. NOD mice, in which the beta2-microglobulin gene has been inactivated by gene targeting (NOD.beta2M-/-), have a deficiency in CD8 T cells and do not develop insulitis, which suggests that CD8 T cells are required for the initiation of T1D. However, neither in humans nor in NOD mice have the immunological requirements for diabetogenic CD8 T cells been precisely defined. In particular, it is not known in which cell type MHC class I expression is required for recruitment and activation of CD8 T cells. Here we have generated transgenic NOD mice, which lack MHC class I on mature professional antigen-presenting cells (pAPCs). These "class I APC-bald" mice developed periislet insulitis but not invasive intraislet insulitis, and they never became diabetic. Recruitment to the islet milieu does not therefore require cognate interaction between CD8 T cells and MHC class I on mature pAPCs. Conversely, such an interaction is critically essential to allow the crucial shift from periislet insulitis to invasive insulitis. Importantly, our findings demonstrate unequivocally that CD8 T cells cannot be primed to become diabetogenic by islet beta cells alone.
de Jersey
James
J
Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, The Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia.
Snelgrove
Sarah L
SL
Palmer
Stephanie E
SE
Teteris
Simon A
SA
Mullbacher
Arno
A
Miller
Jacques F A P
JF
Slattery
Robyn M
RM
D000818:Animals; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping; D007515:Islets of Langerhans / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D009765:Obesity / Q000276:immunology
D017931:DNA Primers