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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Principais autores: Ishigaki, K, Lagattuta, KA, Luo, Y, James, EA, Buckner, JH, Raychaudhuri, S
Formato: Journal article
Idioma:English
Publicado em: Springer Nature 2022
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author Ishigaki, K
Lagattuta, KA
Luo, Y
James, EA
Buckner, JH
Raychaudhuri, S
author_facet Ishigaki, K
Lagattuta, KA
Luo, Y
James, EA
Buckner, JH
Raychaudhuri, S
author_sort Ishigaki, K
collection OXFORD
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 the HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (for example, citrullinated epitope-specific TCRs in patients with rheumatoid arthritis). Together, these results provide genetic evidence supporting the central hypothesis.
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spelling oxford-uuid:6963ac3d-f43f-4065-af6b-db8fa32a37da2022-11-08T15:41:13ZHLA autoimmune risk alleles restrict the hypervariable region of T cell receptorsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6963ac3d-f43f-4065-af6b-db8fa32a37daEnglishSymplectic ElementsSpringer Nature2022Ishigaki, KLagattuta, KALuo, YJames, EABuckner, JHRaychaudhuri, SPolymorphisms 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 the HLA risk alleles are more enriched in candidate pathogenic TCRs than control TCRs (for example, citrullinated epitope-specific TCRs in patients with rheumatoid arthritis). Together, these results provide genetic evidence supporting the central hypothesis.
spellingShingle Ishigaki, K
Lagattuta, KA
Luo, Y
James, EA
Buckner, JH
Raychaudhuri, S
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
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