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

• DOI: 10.1371/journal.pone.0071746
• Publication Date: 2013-08-19T21:18:27Z
• Authors: Cornelia Schuster; Helen Brosi; Katja Stifter; Bernhard O. Boehm; Reinhold Schirmbeck
• Keywords: 0301 basic medicine; Science; Q; Programmed Cell Death 1 Receptor; R; Mice, Transgenic; Bystander Effect; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Diabetes Mellitus, Experimental; Disease Models, Animal; Epitopes; Mice; 03 medical and health sciences; HEK293 Cells; Mutation; Medicine; Animals; Humans; Insulin; Antigens; Protein Precursors; Research Article

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