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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 ORCID: https://orcid.org/0000-0002-2812-8845 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: 20 Oct 2022 07:39
URI: https://orca.cardiff.ac.uk/id/eprint/25988

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