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Regulation of CD8 T cell-mediated diabetes induction by co-inhibitory and co-stimulatory signals delivered by pancreatic beta cells

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129 S.
 
Veröffentlichung
2012-05-16
DOI
10.18725/OPARU-2351

Dissertation

Autoren
Schuster, Cornelia
Fakultäten
Medizinische Fakultät
Lizenz
Standard
https://oparu.uni-ulm.de/xmlui/license_v3
Zusammenfassung
RIP-B7.1 mice expressing the co-stimulatory molecule B7.1 (CD80) on pancreatic beta cells are an attractive model to characterize the de novo induction of preproinsulin (ppins)-specific CD8 T cells and experimental autoimmune diabetes (EAD). Different preproinsulin-encoding vectors selectively induce either insulin Kb/A12-21- (immunization with the ppins antigen) or insulin Kb/B22-29-specific (immunization with a mutant ppins-delta-A12-21 antigen lacking the COOH-terminal A12-21 epitope) CD8 T cells and EAD. In this study, RIP-B7.1 mice were used to characterize the priming conditions of both, Kb/A12-21- and Kb/B22-29-specific CD8 T cells. Only the ppins-delta-A12-21-antigen efficiently elicited Kb/B22-29-specific CD8 T cells and EAD. Modulation of the processing sites at the B/C junction of the ppins-delta-A12-21 antigen by adding specific furin-recognition sites (ppins-furin-delta-A12-21) enhanced priming of Kb/B22-29-specific CD8 T cells and accelerated EAD progression. EAD development by Kb/B22-29-specific CD8 T cells is triggered by co-stimulator (B7.1), but not by co-inhibitor (PD-L1) expression on beta cells. I further established novel immunization strategies (repeated injections of pCI/ppins in short intervals; pre-immunization with a recombinant insulin-expressing AAV followed by pCI/ppins DNA immunization) that could suppress Kb/A12-21-specific diabetes development in PD-L1-/- mice. Similar to the ppins-specific EAD model, a high affine Kb/Ova257-264-specific CD8 T cell response efficiently induced severe EAD in pCI/Ova-immunized RIP-B7.1/RIP-Ovalow (expressing the Ova-antigen and the co-stimulatory B7.1 molecule in beta cells) but not in PDL1-/-/RIP-Ovalow mice (expressing the Ova-antigen in PD-L1-deficient beta cells). Similarly, adoptive transfer of Ova-specific CD8 T cells into RIP-B7.1/RIP-Ovalow but not PDL1-/-/RIP-Ovalow mice induced EAD.
Erstellung / Fertigstellung
2011
Normierte Schlagwörter
Antigen CD8 [GND]
B-Zelle [GND]
Diabetes mellitus, type 1 [MeSH]
Insulin-secreting cells [MeSH]
Schlagwörter
CD8 T cells; Costimulation; EAD
DDC-Sachgruppe
DDC 610 / Medicine & health

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Zitiervorlage

Schuster, Cornelia (2012): Regulation of CD8 T cell-mediated diabetes induction by co-inhibitory and co-stimulatory signals delivered by pancreatic beta cells. Open Access Repositorium der Universität Ulm. Dissertation. http://dx.doi.org/10.18725/OPARU-2351

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