Inhibitory KIRs decrease HLA class II-mediated protection in Type 1 Diabetes
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2024-12-26
Date Acceptance
2024-10-09
Citation
PLoS Genetics, 2024, 20 (12)
ISSN
1553-7390
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Genetics
Volume
20
Issue
12
Copyright Statement
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.
License URL
Subjects
GENETIC SUSCEPTIBILITY
Genetics & Heredity
GENOME-WIDE ASSOCIATION
IMMUNOGLOBULIN-LIKE RECEPTOR
KILLER-CELL RECEPTORS
KIR3DL2
Life Sciences & Biomedicine
LYMPHOID TYROSINE PHOSPHATASE
NK CELLS
RESISTANCE
Science & Technology
T-CELLS
Publication Status
Published
Article Number
e1011456
Date Publish Online
2024-12-26