Graduate MD/PhD Student Harvard Med. Sch., United States
Introduction/Rationale: T cell receptors (TCRs) orchestrate T cell mediated immunity. While the somatic diversification of TCRs has been extensively studied, inherited genetic diversity in the TCR V, D, and J genes has remained poorly characterized due to the complex, repetitive nature of the TCR loci. As a result, the contribution of germline TCR variation to immune diversity and evolution has remained largely unexplored.
Methods: We analyzed long-read whole-genome sequencing from 2,668 globally diverse donors to resolve allelic diversity across TCR genes encoding the α, β, γ, and δ chains. Using a custom bioinformatics pipeline, discovered alleles for each gene from long-read genome assemblies and orthogonally confirmed they were expressed in human repertoires. Population-genetic analyses were applied to detect signatures of natural selection, and single-cell data was used to analyze functional phenotypes.
Results: We generated a near-complete map of human TCR germline diversity, capturing over 94% of common alleles. We discovered 530 novel V gene alleles, representing a 361% increase in the number of known alleles. Nearly every amino acid position within V genes exhibited polymorphism, including chemically divergent residues at antigen-contacting sites. We found pervasive evidence of pathogen-driven natural selection on TCR genes, including diversifying selection across CDR and framework codons, balancing selection on a TRAJ gene critical for anti-influenza responses, and positive selection on a TRAV gene. We find TCR allelic polymorphism alters core functional properties of T cells, including thymic fate commitment, phenotypes in diseased tissues, and cell-surface receptor abundance.
Conclusion: Collectively, our findings position inherited variation in TCR genes as a key axis of immunological diversity that shapes interindividual differences in immune responses. The allelic map we develop enables future studies that study the impact inherited TCR variation across diverse contexts.
