TCR germline diversity reveals evidence of natural selection on variable and joining alpha chain genes 2250859

Abstract Introduction 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. Funding Source NIH grants R01AR063759, P01AI148102, U01HG012009, R56HG013083, and T32GM144273. Topic Categories Computational and Systems Immunology (COMP)