AUTHOR=Zahid H. Jabran , Taniguchi Ruth , Ebert Peter , Chow I-Ting , Gooley Chris , Lv Jinpeng , Pisani Lorenzo , Rusnak Mikaela , Elyanow Rebecca , Takamatsu Hiroyuki , Zhou Wenyu , Greissl Julia , Robins Harlan , Carlson Jonathan M. 

TITLE=Large-scale statistical mapping of T-cell receptor β sequences to human leukocyte antigens

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1603730

DOI=10.3389/fimmu.2025.1603730

ISSN=1664-3224

ABSTRACT=IntroductionT-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.MethodsWe statistically associated approximately 106 public TCRβs to specific HLAs using TCRβ repertoires sampled from 4,144 HLA-genotyped subjects. The TCRβs we associated were specific to unique HLA allotypes, not allelic groups, and to the paired α–β heterodimer of class II HLAs, though exceptions were observed.ResultsThis specificity permitted highly accurate imputation of 248 class I and II HLAs from the TCRβ repertoire. Notably, 45 HLA-DP and -DQ heterodimers lacked associated TCRs because they likely arise from non-functional trans-complementation. The public class I and II HLA-associated TCRβs we identified were primarily expressed on CD8+ and CD4+ memory T cells, respectively, which were responding to various common antigens.DiscussionOur results recapitulate fundamental biology, provide insights into the functionality of HLAs, and demonstrate the power and potential of population-level TCRβ repertoire sequencing.