Long-term maintenance of human naïve T cells through in situ homeostasis in lymphoid tissue sites

Naive T cells develop in the thymus and coordinate immune responses to new antigens; however, mechanisms for their long-term persistence over the human life span remain undefined. We investigated human naive T cell development and maintenance in primary and secondary lymphoid tissues obtained from individual organ donors aged 2 months to 73 years. In the thymus, the frequency of double-positive thymocytes declined sharply in donors >40 years of age, coincident with reduced recent thymic emigrants in lymphoid tissues, whereas naive T cells were functionally maintained predominantly in lymph nodes (LNs). Analysis of T cell receptor clonal distribution by CDR3 sequencing of naive CD4 + and CD8 + T cells in spleen and LNs reveals site-specific clonal expansions of naive T cells from individuals >40 years of age, with minimal clonal overlap between lymphoid tissues. We also identified biased naive T cell clonal distribution within specific LNs on the basis of VJ usage. Together, these results suggest prolonged maintenance of naive T cells through in situ homeostasis and retention in lymphoid tissue.