Zahid, H. J.; Taniguchi, R.; Ebert, P.; Chow, I.-T.; Gooley, C.; Lv, J.; Pisani, L.; Rusnak, M.; Elyanow, R.; Takamatsu, H.; Zhou, W.; Greissl, J.; Robins, H.; Carlson, J. M.

Interactions between diverse sets of T-cell receptors (TCRs) and 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 use the TCR{beta} repertoire of 4,144 HLA-genotyped subjects to associate [~]10^6 public TCRs (i.e., TCRs observed in multiple subjects) with specific HLAs, providing a new window into the functional characteristics of HLAs. We find that the vast majority of these HLA-associated public TCRs are specific to unique HLA allotypes, not allelic groups, and to the paired -{beta} heterodimer of class II HLAs though we observe some exceptions and also that the breadth of the TCR response is proportional to HLA zygosity. Identification of public HLA-specific TCRs permits highly accurate imputation of 248 class I and II HLAs from the TCR{beta} repertoire alone. Notably, 45 HLA-DP and -DQ heterodimers cannot be imputed due to a lack of associated TCRs, despite high representation in our training set. Gene linkage analysis indicates these heterodimers primarily arise from trans-complementation resulting in non-functional -{beta} pairs. Cell sorting, clonal expansion, and comparisons between SARS-CoV-2-exposed and -naive populations suggest that public class I and class II HLA-associated TCRs we identify are primarily expressed on CD8+ and CD4+ memory T cells, respectively, which are responding to a mix of common antigens. Our results recapitulate fundamental immunology, provide critical new insights into the functionality of HLAs, and demonstrate the power and potential of population-level TCR repertoire sequencing.