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Immunotargeting of insulin reactive CD8 T cells to prevent diabetes

Scott, Gwen S., Fishman, Sigal, Siew, Lai Khai, Margalit, Alon, Chapman, Stephen, Chervonsky, Alexander V., Wen, Li, Gross, Gideon and Wong, Florence Susan 2010. Immunotargeting of insulin reactive CD8 T cells to prevent diabetes. Journal of Autoimmunity 35 (4) , pp. 390-397. 10.1016/j.jaut.2010.08.005

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
Uncontrolled Keywords: rodent, cytotoxic T cells, diabetes, cytotoxicity
Publisher: Elsevier
ISSN: 0896-8411
Last Modified: 04 Jun 2017 03:45
URI: http://orca.cf.ac.uk/id/eprint/25988

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