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

Kazuyoshi Ishigaki; Kaitlyn A Lagattuta; Yang Luo; Eddie A James; Jane H Buckner; Soumya Raychaudhuri

doi:10.1038/s41588-022-01032-z

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

Nat Genet. 2022 Apr;54(4):393-402. doi: 10.1038/s41588-022-01032-z. Epub 2022 Mar 24.

Authors

Kazuyoshi Ishigaki^{1

2

3

4}, Kaitlyn A Lagattuta^{1

2

3

5

6}, Yang Luo^{1

2

3}, Eddie A James⁷, Jane H Buckner⁷, Soumya Raychaudhuri^{8

9

10

11

12}

Affiliations

¹ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
² Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁵ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁶ Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA.
⁷ Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
⁸ Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
⁹ Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁰ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
¹¹ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. [email protected].
¹² Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alleles
Amino Acids / genetics
Autoimmune Diseases* / genetics
Complementarity Determining Regions / genetics
HLA-DRB1 Chains / genetics
HLA-DRB1 Chains / metabolism
Humans
Receptors, Antigen, T-Cell* / genetics
Receptors, Antigen, T-Cell* / metabolism

Substances

Amino Acids
Complementarity Determining Regions
HLA-DRB1 Chains
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding