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

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.

We 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.

This 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.

Our results recapitulate fundamental biology, provide insights into the functionality of HLAs, and demonstrate the power and potential of population-level TCRβ repertoire sequencing.