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

Introduction 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. Methods We statistically associated approximately 10 6 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. Results 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. Discussion Our results recapitulate fundamental biology, provide insights into the functionality of HLAs, and demonstrate the power and potential of population-level TCRβ repertoire sequencing.