Characterization of preproinsulin (ppins)-specific CD8 T cell responses in novel models of autoimmune diabetes
Auch gedruckt in der BibliothekZ: J-H 13.720; W: W-H 12.166
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2010-07-09
RIP-B7.1 mice expressing the co-stimulator molecule B7.1 (CD80) on pancreatic beta cells are a well-established model to characterize de novo induction of autoreactive, insulin-specific CD8 T cells and experimental autoimmune diabetes (EAD). Preproinsulin (ppins)-encoding vectors efficiently induced EAD in RIP-B7.1 mice. In this study, RIP-B7.1 mice were used to explore the priming requirements of diabetogenic, insulin-specific CD8 T cells. Targeting the ppins into the ER was a prerequisite to efficiently prime diabetogenic CD8 T cells. Thus, direct loading of the epitope on newly synthesized Kb-molecules in the ER may be an essential step for enabling presentation of this low affine epitope to diabetogenic CD8 T cells. The study showed that immunodominance hierarchies operated in professional antigen presenting cells but not on insulin-producing target cells. Co-priming of Kb restricted viral or OVA-specific CD8 T cell responses at the same site of antigen delivery prevented priming of ppins-specific, diabetogenic CD8 T cells. CD8 T cell-mediated immunodominance hierarchies also operated within the ppins antigen. A novel mouse model to study the pathogenic crosstalk between insulin-specific CD8 T cells with pancreatic target cells was established. It is known that the PD-1/PD-L1 signaling pathway regulates the balance between T cell activation, tolerance and immunopathology. EAD was efficiently induced in B6 mice by DNA-based immunization after antibody-mediated PD-L1 blockade. Using PD-L1 KO, PD-1 KO and bone marrow chimeric mice showed that binding of PD-1 on activated T cells to PD-L1 expressed by pancreatic beta cells may down modulate the diabetogenic potential of ppins-specific CD8 T cells. Co-stimulator and co-inhibitor molecule expression by epitope-presenting cells can hence modulate their susceptibility to be attacked by autoagressive CD8 T cells and thereby ultimately determine the course of autoimmune disease.
LizenzStandard (ohne Print-On-Demand)
Diabetes mellitus, type 1