ORIGINAL RESEARCH article
Front. Immunol.
Sec. T Cell Biology
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1603730
Large-scale statistical mapping of T-cell receptor β sequences to Human Leukocyte Antigens
Provisionally accepted
- Microsoft Research (United States), Redmond, United States
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T-cell receptors (TCRs) interacting with peptides presented by human leukocyte antigens (HLAs) are the foundation of the adaptive immune system but population-level analysis of TCR-HLA interactions is lacking. Here we statistically associate ∼10 6 public TCRs to specific HLAs using the TCRβ repertoires sampled from 4,144 HLA-genotyped subjects. The TCRs we associate are specific to unique HLA allotypes, not allelic groups, and to the paired α-β heterodimer of class II HLAs though exceptions are observed. This specificity permits highly accurate imputation of 248 class I and II HLAs from the TCRβ repertoire. Notably, 45 HLA-DP and -DQ heterodimers lack associated TCRs 1 because they likely arise from non-functional trans-complementation. The public class I and II HLA-associated TCRs we identify are primarily expressed on CD8 + and CD4 + memory T cells, respectively, which are responding to various common antigens. Our results recapitulate fundamental biology, provide insights into the functionality of HLAs and demonstrate the power and potential of population-level TCR repertoire sequencing.
Keywords: human leukocyte antigen, T cell, immunology, T cell - HLA interaction, Antigen Presentation
Received: 31 Mar 2025; Accepted: 31 Jul 2025.
Copyright: © 2025 Zahid. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Harus Jabran Zahid, Microsoft Research (United States), Redmond, United States
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