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Coinhibitory PD-1/PD-L1 (B7-H1) interactions provide critical signals for the regulation of autoreactive T-cell responses. We established mouse models, expressing the costimulator molecule B7.1 (CD80) on pancreatic beta cells (RIP-B7.1 tg mice) or are deficient in coinhibitory PD-L1 or PD-1 molecules (PD-L1 −/−  and PD-1 −/−  mice), to study induction of preproinsulin (ppins)-specific CD8 T-cell responses and experimental autoimmune diabetes (EAD) by DNA-based immunization. RIP-B7.1 tg mice allowed us to identify two CD8 T-cell specificities: pCI/ppins DNA exclusively induced K b /A 12–21 -specific CD8 T-cells and EAD, whereas pCI/ppinsΔA 12–21  DNA (encoding ppins without the COOH-terminal A 12–21  epitope) elicited K b /B 22–29 -specific CD8 T-cells and EAD. Specific expression/processing of mutant ppinsΔA 12–21  (but not ppins) in non-beta cells, targeted by intramuscular DNA-injection, thus facilitated induction of K b /B 22–29 -specific CD8 T-cells. The A 12–21  epitope binds K b  molecules with a very low avidity as compared with B 22–29 . Interestingly, immunization of coinhibition-deficient PD-L1 −/−  or PD-1 −/−  mice with pCI/ppins induced K b /A 12–21 -monospecific CD8 T-cells and EAD but injections with pCI/ppinsΔA 12–21  did neither recruit K b /B 22–29 -specific CD8 T-cells into the pancreatic target tissue nor induce EAD. PpinsΔA 12–21 /(K b /B 22–29 )-mediated EAD was efficiently restored in RIP-B7.1 + /PD-L1 −/−  mice, differing from PD-L1 −/−  mice only in the tg B7.1 expression in beta cells. Alternatively, an ongoing beta cell destruction and tissue inflammation, initiated by ppins/(K b /A 12–21 )-specific CD8 T-cells in pCI/ppins+pCI/ppinsΔA 12–21  co-immunized PD-L1 −/−  mice, facilitated the expansion of ppinsΔA 12–21 /(K b /B 22–29 )-specific CD8 T-cells. CD8 T-cells specific for the high-affinity K b /B 22–29 - (but not the low-affinity K b /A 12–21 )-epitope thus require stimulatory ´help from beta cells or inflamed islets to expand in PD-L1-deficient mice. The new PD-1/PD-L1 diabetes models may be valuable tools to study under well controlled experimental conditions distinct hierarchies of autoreactive CD8 T-cell responses, which trigger the initial steps of beta cell destruction or emerge during the pathogenic progression of EAD.

A Missing PD-L1/PD-1 Coinhibition Regulates Diabetes Induction by Preproinsulin-Specific CD8 T-Cells in an Epitope-Specific Manner