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HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors

Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provide...

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Autores principales: Ishigaki, Kazuyoshi, Lagattuta, Kaitlyn, Luo, Yang, James, Eddie, Buckner, Jane H., Raychaudhuri, Soumya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010379/
https://www.ncbi.nlm.nih.gov/pubmed/35332318
http://dx.doi.org/10.1038/s41588-022-01032-z
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author Ishigaki, Kazuyoshi
Lagattuta, Kaitlyn
Luo, Yang
James, Eddie
Buckner, Jane H.
Raychaudhuri, Soumya
author_facet Ishigaki, Kazuyoshi
Lagattuta, Kaitlyn
Luo, Yang
James, Eddie
Buckner, Jane H.
Raychaudhuri, Soumya
author_sort Ishigaki, Kazuyoshi
collection PubMed
description Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA-CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (e.g., citrullinated-epitope-specific TCRs in rheumatoid arthritis patients). Together, these results provide novel genetic evidence supporting the central hypothesis.
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spelling pubmed-90103792022-09-24 HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors Ishigaki, Kazuyoshi Lagattuta, Kaitlyn Luo, Yang James, Eddie Buckner, Jane H. Raychaudhuri, Soumya Nat Genet Article Polymorphisms in the human leukocyte antigen (HLA) genes strongly influence autoimmune disease risk. HLA risk alleles may influence thymic selection to increase the frequency of T cell receptors (TCRs) reactive to autoantigens (central hypothesis). However, research in human autoimmunity has provided little evidence supporting the central hypothesis. Here we investigated the influence of HLA alleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), which confers antigen recognition. We observed unexpectedly strong HLA-CDR3 associations. The strongest association was found at HLA-DRB1 amino acid position 13, the position that mediates genetic risk for multiple autoimmune diseases. We identified multiple CDR3 amino acid features enriched by HLA risk alleles. Moreover, the CDR3 features promoted by HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (e.g., citrullinated-epitope-specific TCRs in rheumatoid arthritis patients). Together, these results provide novel genetic evidence supporting the central hypothesis. 2022-04 2022-03-24 /pmc/articles/PMC9010379/ /pubmed/35332318 http://dx.doi.org/10.1038/s41588-022-01032-z Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
spellingShingle Article
Ishigaki, Kazuyoshi
Lagattuta, Kaitlyn
Luo, Yang
James, Eddie
Buckner, Jane H.
Raychaudhuri, Soumya
HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title_full HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title_fullStr HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title_full_unstemmed HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title_short HLA autoimmune risk alleles restrict the hypervariable region of T cell receptors
title_sort hla autoimmune risk alleles restrict the hypervariable region of t cell receptors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010379/
https://www.ncbi.nlm.nih.gov/pubmed/35332318
http://dx.doi.org/10.1038/s41588-022-01032-z
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