Original Data

Incomplete Killing And Enhanced Activation of Islet-Reactive CD8+ T Cells by FasL-Expressing Dendritic Cells Limits Protection from Diabetes

Mikael Maksimow^1,2, Catharina Alam¹, Arno Hänninen¹

Manuscript submitted September 23, 2008; resubmitted November 11, 2008; accepted November 26, 2008.

Keywords: type 1 diabetes, autoimmunity, dendritic cell, FasL, CD8, islet-antigen, tolerance, vaccination

Abstract

AIMS: Autologous dendritic cells (DC) are a promising tool for induction of cytotoxic CD8+ T cell immunity against tumors and chronic viral infections. When armed with the death-inducing Fas-ligand (FasL, CD195), DC attenuate delayed-type hypersensitivity reactions and allotransplant rejection by promoting activation-induced cell death in T cells. We investigated the possibility of using FasL-expressing DC to induce deletion of islet-reactive CD8+ T cells in vivo, and to prevent destruction of pancreatic islets in a model of autoimmune diabetes. METHODS: DC, propagated from mouse bone marrow cells, were purified and made to express FasL and islet-antigen via plasmid transfection. CD8+ T cells (OT-I cells) recognizing the antigen, ovalbumin, were adoptively transferred to transgenic mice expressing ovalbumin in islets (RIP-OVA^lo mice), and these mice were primed with ovalbumin. To test the potential of DC to prevent diabetes in this model, the mice were later intravenously vaccinated with the transfected DC. RESULTS: Transfected DC induced partial deletion of antigen-reactive CD8+ T cells in vivo and reduced the level of lymphocyte infiltration into pancreatic islets. Diabetes developed less frequently in vaccinated mice, but this effect was limited. Further in vitro analysis showed that FasL-expressing DC not only deleted many of the responding CD8+ T cells but also promoted the expansion of surviving cells and their IFN-γ production. CONCLUSIONS: FasL-expressing DC can also have stimulatory effects on CD8+ T cells warranting further investigation into the optimal design of tolerance-promoting DC-vaccination to prevent autoimmune diabetes.

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