Immunotargeting of insulin reactive CD8 T cells to prevent Diabetes

Abstract

Insulin is one of the earliest targeted autoantigens in the immune destruction of insulin-producing beta cells by autoreactive CD4 and CD8 T cells in type 1 diabetes. In this study, we used Non-obese diabetic (NOD) transgenic T cells engineered to express MHC class I-insulin peptide complexes linked to a T cell activation component (InsCD3-ζ), to target insulin-reactive CD8 T cells. We showed that activated, but not naïve, InsCD3-ζ CD8 T cells killed diabetogenic insulin-reactive CD8 target cells in vitro, inducing antigen-specific cell death mediated via both the release of perforin and the Fas–Fas ligand pathway. In vivo, InsCD3-ζ CD8 T cells migrated to the pancreatic lymph nodes of NOD mice after adoptive transfer. Concomitant with this, infiltration of CD8 T cells was also reduced in the pancreatic islets. Finally, in vivo, we showed that diabetes induced by adoptive transfer of insulin-reactive T cells was reduced following injection of activated InsCD3-ζ CD8 T cells. Furthermore, young NOD mice injected with InsCD3-ζ CD8 T cells developed a lower incidence and delayed onset of diabetes. Thus, using this novel system we have demonstrated that InsCD3-ζ CD8 T cells can directly kill insulin-reactive CD8 T cells in vitro and by targeting insulin-specific CD8 T cells early in the course of disease alter the progression of spontaneous diabetes in vivo in NOD mice.