Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes.

Mora-Bitria, Laura, Debebe, Bisrat J., Miners, Kelly L., Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Kaur, Charandeep, Traherne, James A., Jiang, Wei, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Hadcocks, Linda, McQuibban, Nicholas A. R., Trowsdale, John, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845, Pontikos, Nikolas, Niederalt, Christoph and Asquith, Becca 2024. Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes. PLoS Genetics 20 (12) , e1011456. 10.1371/journal.pgen.1011456

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Abstract

Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer (NK) cells and late-stage differentiated T cells. There is accumulating evidence that iKIRs regulate T cell-mediated immunity. Recently, we reported that T cell-mediated control was enhanced by iKIRs in chronic viral infections. We hypothesized that in the context of autoimmunity, where an enhanced T cell response might be considered detrimental, iKIRs would have an opposite effect. We studied Type 1 diabetes (T1D) as a paradigmatic example of autoimmunity. In T1D, variation in the Human Leucocyte Antigen (HLA) genes explains up to 50% of the genetic risk, indicating that T cells have a major role in T1D etiopathogenesis. To investigate if iKIRs affect this T cell response we asked whether HLA associations were modified by iKIR genes. We conducted an immunogenetic analysis of a case-control T1D dataset (N = 11,961) and found that iKIR genes, in the presence of genes encoding their ligands, have a consistent and significant effect on protective HLA class II genetic associations. Our results were validated in an independent data set. We conclude that iKIRs significantly decrease HLA class II protective associations and suggest that iKIRs regulate CD4+ T cell responses in T1D. [Abstract copyright: Copyright: © 2024 Mora-Bitria et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.]

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Public Library of Science
ISSN:	1553-7390
Date of First Compliant Deposit:	10 January 2025
Date of Acceptance:	9 October 2024
Last Modified:	10 Jan 2025 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/175182

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