Abstract
The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23-dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Proliferation / drug effects
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Cells, Cultured
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Flow Cytometry
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HEK293 Cells
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HeLa Cells
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Humans
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Immunoblotting
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Inflammatory Bowel Diseases / genetics
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Inflammatory Bowel Diseases / immunology
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Inflammatory Bowel Diseases / metabolism
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-22
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Interleukin-23 / pharmacology
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Interleukins / immunology
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Interleukins / metabolism
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Luciferases / genetics
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Luciferases / metabolism
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Polymorphism, Single Nucleotide / immunology*
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Receptors, Interleukin / genetics
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Receptors, Interleukin / immunology*
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Receptors, Interleukin / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Th17 Cells / metabolism
Substances
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IL23R protein, human
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Interleukin-17
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Interleukin-23
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Interleukins
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Receptors, Interleukin
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STAT3 Transcription Factor
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Interferon-gamma
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Luciferases