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

doi:10.1371/journal.pgen.1011456

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

2024-12-26

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Nicholas A. R. McQuibban

DOI：10.1371/journal.pgen.1011456

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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.

Keywords:

LYMPHOID TYROSINE PHOSPHATASE

IMMUNOGLOBULIN-LIKE RECEPTOR

GENOME-WIDE ASSOCIATION

KILLER-CELL RECEPTORS

T-CELLS

GENETIC SUSCEPTIBILITY

C LIGAND

NK CELLS

KIR3DL2

RESISTANCE

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

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