Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes

Wong, Florence Susan ORCID: https://orcid.org/0000-0002-2812-8845, Siew, Lai Khai, Scott, Gwen, Thomas, Ian J., Chapman, Stephen, Viret, Christopher and Wen, Li 2009. Activation of insulin-reactive CD8 T-cells for development of autoimmune diabetes. Diabetes 58 (5) , pp. 1156-1164. 10.2337/db08-0800

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Abstract

Objective: We have previously reported a highly diabetogenic CD8 T cell clone, G9C8, in the Non Obese Diabetic (NOD) mouse, specific to low avidity insulin peptide B15-23 and cells responsive to this antigen are among the earliest islet infiltrates. We aimed to study the selection, activation and development of diabetogenic capacity of these insulin-reactive T cells. Research Design and Methods: We generated a TCR transgenic mouse expressing the cloned TCR Vα18/Vβ6 receptor of the G9C8 insulin-reactive CD8 T cell clone. The mice were crossed to TCRCα−/− mice so that the majority of the T cells expressed the clonotypic TCR and the phenotype and function of the cells was investigated. Results: There was good selection of CD8 T cells with a predominance of CD8 single positive thymocytes, in spite of thymic insulin expression. Peripheral lymph node T cells had a naïve phenotype (CD44lo, CD62Lhi) and proliferated to insulin B15-23 peptide and to insulin. These cells produced interferon-γ and TNF-α in response to insulin peptide and were cytotoxic to insulin-peptide coated targets. In vivo, the TCR transgenic mice developed insulitis but not spontaneous diabetes. However, the mice developed diabetes on immunization, and the activated transgenic T cells were able to transfer diabetes to immunodeficient NOD.scid mice. Conclusion: Autoimmune CD8 T cells responding to a low affinity insulin B chain peptide escape from thymic negative selection, and require activation in vivo to cause diabetes.

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
Publisher:	American Diabetes Association
ISSN:	0012-1797
Last Modified:	20 Oct 2022 08:57
URI:	https://orca.cardiff.ac.uk/id/eprint/30159

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