ArticlePloS one2013
A missing PD-L1/PD-1 coinhibition regulates diabetes induction by preproinsulin-specific CD8 T-cells in an epitope-specific manner.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed, 6 citations in OpenAlex.
- Dextran Sulfate Protects Pancreatic β-Cells, Reduces Autoimmunity, and Ameliorates Type 1 Diabetes.Diabetes · 2020Article
- Preproinsulin Designer Antigens Excluded from Endoplasmic Reticulum Suppressed Diabetes Development in NOD Mice by DNA Vaccination.Molecular therapy. Methods & clinical development · 2019Article
- Exploring the induction of preproinsulin-specific Foxp3(+) CD4(+) Treg cells that inhibit CD8(+) T cell-mediated autoimmune diabetes by DNA vaccination.Scientific reports · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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