Regulation of CD8 T cell-mediated diabetes induction by co-inhibitory and co-stimulatory signals delivered by pancreatic beta cells
RIP-B7.1 mice expressing the co-stimulatory molecule B7.1 (CD80) on pancreatic beta cells are an attractive model to characterize the de novo induction of preproinsulin (ppins)-specific CD8 T cells and experimental autoimmune diabetes (EAD). Different preproinsulin-encoding vectors selectively induce either insulin Kb/A12-21- (immunization with the ppins antigen) or insulin Kb/B22-29-specific (immunization with a mutant ppins-delta-A12-21 antigen lacking the COOH-terminal A12-21 epitope) CD8 T cells and EAD. In this study, RIP-B7.1 mice were used to characterize the priming conditions of both, Kb/A12-21- and Kb/B22-29-specific CD8 T cells. Only the ppins-delta-A12-21-antigen efficiently elicited Kb/B22-29-specific CD8 T cells and EAD. Modulation of the processing sites at the B/C junction of the ppins-delta-A12-21 antigen by adding specific furin-recognition sites (ppins-furin-delta-A12-21) enhanced priming of Kb/B22-29-specific CD8 T cells and accelerated EAD progression. EAD development by Kb/B22-29-specific CD8 T cells is triggered by co-stimulator (B7.1), but not by co-inhibitor (PD-L1) expression on beta cells. I further established novel immunization strategies (repeated injections of pCI/ppins in short intervals; pre-immunization with a recombinant insulin-expressing AAV followed by pCI/ppins DNA immunization) that could suppress Kb/A12-21-specific diabetes development in PD-L1-/- mice. Similar to the ppins-specific EAD model, a high affine Kb/Ova257-264-specific CD8 T cell response efficiently induced severe EAD in pCI/Ova-immunized RIP-B7.1/RIP-Ovalow (expressing the Ova-antigen and the co-stimulatory B7.1 molecule in beta cells) but not in PDL1-/-/RIP-Ovalow mice (expressing the Ova-antigen in PD-L1-deficient beta cells). Similarly, adoptive transfer of Ova-specific CD8 T cells into RIP-B7.1/RIP-Ovalow but not PDL1-/-/RIP-Ovalow mice induced EAD.
Erstellung / Fertigstellung
Normierte SchlagwörterAntigen CD8 [GND]
Diabetes mellitus, type 1 [MeSH]
Insulin-secreting cells [MeSH]