TCR2HLA: Calibrated inference of HLA genotypes from TCR repertoires enables identification of immunologically relevant metaclonotypes

Year: 2026

Type: article

Abstract: T cell receptors (TCRs) recognize peptides presented by polymorphic human leukocyte antigen (HLA) molecules, but HLA genotype data are often missing from TCR repertoire sequencing studies. To address this, we developed TCR2HLA, an open-source tool that infers HLA genotypes from TCRβ repertoires. Expanding on work linking public TRBV-CDR3 sequences to HLA genotypes, we incorporated "quasi-public" metaclonotypes - composed of rarer TCRβ sequences with shared amino acid features - enriched by HLA genotypes. Using four TCRβseq datasets from 3,150 individuals, we applied TRBV gene partitioning and locality-sensitive hashing to identify ~96,000 TCRβ features strongly associated with specific HLA alleles from 71M input TCRs. Binary HLA classifiers built with these features achieved high balanced accuracy (>0.9) across common HLA-A (9/12), B (9/12), C (6/13), DRB1 (11/11) alleles and prevalent DPA1/DPB1 (6/10), DQA1/DQB1 (8/17) heterodimers. We also introduced a high-sensitivity calibration to support predictions in samples with as few as 5,000 unique clonotypes. Calibrated predictions with confidence filtering improved reliability. Beyond genotype imputation, TCR2HLA enables the discovery of novel HLA- and exposure-associated TCRs, as shown by the identification of SARS-CoV-2 related TCRs in a large COVID-19 dataset lacking HLA data. TCR2HLA provides a scalable framework for bridging the gap between TCRseq data and HLA genotype for biomarker discovery.

Source: PLoS Computational Biology

DOI: 10.1371/journal.pcbi.1013767

Authors: Koshlan Mayer-Blackwell, Anastasia Minervina, Mikhail Pogorelyy, Puneet Rawat, Melanie R. Shapiro, Leeana D. Peters, Emily S. Ford, Amanda L. Posgai, Kasi Vengesana, Samuel Minot, David M. Koelle, Victor Greiff, Philip Bradley, Todd M. Brusko, Paul G. Thomas, Andrew Fiore-Gartland

Institutions: Fred Hutch Cancer Center, St. Jude Children's Research Hospital, Oslo University Hospital, University of Oslo, University of Florida, University of Washington, Benaroya Research Institute

Language: English

Topic: vaccines and immunoinformatics approaches

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,043

Funders: American Diabetes Association, Bill and Melinda Gates Foundation, Leona M. and Harry B. Helmsley Charitable Trust, American Lebanese Syrian Associated Charities, European Commission, Norges Forskningsråd, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Office of Research Infrastructure Programs, National Institutes of Health

OpenAlex ID: W7124428692