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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.
AuthorsCornelia Schuster, Helen Brosi, Katja Stifter, Bernhard O Boehm, Reinhold Schirmbeck
JournalPloS one (PLoS One) Vol. 8 Issue 8 Pg. e71746 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23977133 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Epitopes
  • Insulin
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Protein Precursors
  • preproinsulin
Topics
  • Animals
  • Antigens (metabolism)
  • B7-H1 Antigen (antagonists & inhibitors, metabolism)
  • Bystander Effect (immunology)
  • CD8-Positive T-Lymphocytes (immunology)
  • Diabetes Mellitus, Experimental (immunology, pathology)
  • Disease Models, Animal
  • Epitopes (immunology)
  • HEK293 Cells
  • Humans
  • Insulin (metabolism)
  • Mice
  • Mice, Transgenic
  • Mutation (genetics)
  • Programmed Cell Death 1 Receptor (antagonists & inhibitors, metabolism)
  • Protein Precursors (metabolism)

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