TCR repertoire shaping of naïve T cell subsets in human ontogeny

T cell receptor (TCR) repertoire analysis provides crucial insight into the maturation of the adaptive immune system. In this study, we examined the diversity and structure of TCRβ repertoire in the sorted naïve CD4⁺, naïve CD8⁺, and naïve regulatory T cell (Treg) subsets from umbilical cord blood (UCB) at early gestation (24–29 weeks), term (38–39 weeks), and late-born neonates (40–42 weeks), as well as from peripheral blood of children, adults, and older individuals. UCB TCRβ repertoires were characterized by shorter CDR3 regions, increased repertoire convergence, and a higher abundance of public clonotypes, consistent with limited junctional diversity in early development. Our data suggest progressive maturation of the UCB TCRβ repertoire with noticeable changes by late gestation (~29 weeks). Notably, UCB-derived naïve Treg cells displayed distinct TCRβ repertoire features compared with adult Treg cells, indicating subset-specific differences in TCRβ repertoire shaping. Across age groups, we observed an age-dependent shift in TCRβ repertoire structure associated with changes in TRBV gene usage with a progressive decrease in the predicted binding strength of CDR2, particularly in repertoires of naïve Treg and naïve CD8⁺ T cells. Together, these results provide insights into TCRβ repertoire formation during human ontogeny and highlight subset-specific trajectories during early life.