Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of Proinsulin-specific CD8+ T-Cells in type 1 diabetes

Thayer, Terri C., Davies, Joanne, Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269, Hanna, Stephanie J., Wen, Li and Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 2021. Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of Proinsulin-specific CD8+ T-Cells in type 1 diabetes. Diabetes 70 (2) , pp. 529-537. 10.2337/db19-1050

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Abstract

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8+T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα-/-CD8+T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα-/-CD8+T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date of Acceptance:	26 October 2020
Last Modified:	07 Feb 2023 02:05
URI:	https://orca.cardiff.ac.uk/id/eprint/136702

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