T cell receptors (TCR) orchestrate adaptive immunity, yet the complex, repetitive architecture of the TCR loci has impeded systematic characterization of human genetic variation in the genes encoding the TCR. Using public long-read sequencing data from the Human Pangenome Reference Consortium and All of Us consortia spanning 2719 donors, we build a near-complete map of common alleles in TCR V, D, and J genes, revealing amino acid variation at almost every position within V genes. We observe allele frequency differences between populations for many individual TCR genes. We present evidence of natural selection on TCR genes, including signals of balancing selection and positive selection in the alpha chain locus. We find TCR allelic polymorphism alters core functional properties of T cells, including thymic fate commitment and cell-surface receptor abundance. Collectively, these findings position inherited variation in TCR genes as a key axis of immunological diversity that may shape interindividual differences in immune responses. In this study, population-scale long-read sequencing reveals extensive germline polymorphism in T cell receptor V and J genes. This variation carries signatures of natural selection and shapes single-cell T cell phenotypes, underscoring its functional importance.
Mantena et al. (Sat,) studied this question.