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Nat Genet DOI:10.1038/s41588-022-01032-z

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

Publication TypeJournal Article
Year of Publication2022
AuthorsIshigaki, K, Lagattuta, KA, Luo, Y, James, EA, Buckner, JH, Raychaudhuri, S
JournalNat Genet
Date Published2022 Mar 24
ISSN1546-1718
Abstract

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.

DOI10.1038/s41588-022-01032-z
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/35332318?dopt=Abstract

Alternate JournalNat Genet
PubMed ID35332318
Grant ListAR063759-05 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
U01-HG009379-04 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
U19-AI111224-06 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
T32GM007753 / / U.S. Department of Health & Human Services | National Institutes of Health (NIH) /
NA / / Uehara Memorial Foundation /