Nonlinear and sex-specific remodeling of the TCRβ repertoire across adulthood

Aging is accompanied by progressive remodeling of the T cell compartment, yet the age-associated dynamics of the TCRβ repertoire, particularly across adulthood, and their sex-specific patterns remain incompletely understood. Here, we profiled the T-cell receptor β-chain (TCRβ) repertoires from 4,527 healthy individuals to characterize age-associated trajectories of the TCRβ repertoire. TCRβ repertoire diversity declines nonlinearly with age, with males exhibiting a pronounced contraction during early adulthood, while females display a more gradual decline. Despite these differences, both sexes display consistent shifts in V and J gene usage and preservation of stable public clonotypes. TCR convergence increases with age, which may reflect changes in T-cell subset composition and selective clonal expansion, consistent with age-associated immune remodeling of the TCRβ repertoire across adulthood. We next developed a TCRβ repertoire-based age prediction model, yielding a TCRβ-derived (predicted) age that showed a modest positive association with chronological age. Together, these findings delineate shared and sex-specific features of TCRβ repertoire remodeling across adulthood and provide a framework for further evaluating the relationship between TCRβ-derived age and independent measures of biological aging.