Highly diverse repertoires of T cell antigen receptors (TCRs) arise from somatic combinatorial rearrangement of variable-diversity-joining gene segments encoding TCR chains. It remains controversial, however, whether germline-encoded variants can select for particular TCR–major histocompatibility complex (MHC) interactions. In Nature Genetics, Sharon et al. utilize expression-quantitative-trait-locus mapping to analyze the expression of TCR-encoding genes in a large human cohort of European ancestry. They identify multiple highly significant MHC-TCR genetic associations indicative of selective pressure for distinct contact interactions. These contacts are especially significant for variable-region-encoded complementarity-determining regions CDR1 and CDR2 of the TCRα chains that interact with HLA-B chains. These findings support the hypothesis that germline contributions influence the recognition of MHC molecules by TCRs and the selection of expressed TCR repertoires, which results in distinct combinations of TCR-MHC interactions.

Nat. Genet. (1 August 2016) doi:10.1038/ng.3625