title: A missing PD-L1/PD-1 coinhibition regulates diabetes induction by preproinsulin-specific CD8 T-cells in an epitope-specific manner.
abstract: 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.
authors: Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
authors: Cornelia
authors: C
authors: Schuster
authors: Helen
authors: H
authors: Brosi
authors: Katja
authors: K
authors: Stifter
authors: Bernhard O
authors: BO
authors: Boehm
authors: Reinhold
authors: R
authors: Schirmbeck
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024201:Bystander Effect / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*
chemical_list: D000941:Antigens; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D000939:Epitopes; D007328:Insulin; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011498:Protein Precursors; C013737:preproinsulin
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