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

Human naïve T cells are maintained in lymph nodes for decades and clonally expand in situ after cessation of thymopoiesis. T cell life doesn’t end at 40 Naïve T cells develop in the thymus. Although thymic function declines with age, T cells are persistent throughout the human life span. Thome et al. examined human lymphoid tissues from donors ranging from 2 months to 73 years in age. They found that, although the number of double-positive thymocytes and recent thymic emigrants dropped in individuals >40 years of age, naïve T cells were functionally maintained in the lymph nodes. There was minimal overlap in clonotype between the lymph tissues, suggesting that lymph nodes may maintain a diverse set of T cell specificities. These data suggest that location really does matter—tissue compartmentalization and homeostasis are critical for maintaining naïve T cells throughout the human life span. Naïve 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 naïve 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 naïve T cells were functionally maintained predominantly in lymph nodes (LNs). Analysis of T cell receptor clonal distribution by CDR3 sequencing of naïve CD4+ and CD8+ T cells in spleen and LNs reveals site-specific clonal expansions of naïve T cells from individuals >40 years of age, with minimal clonal overlap between lymphoid tissues. We also identified biased naïve T cell clonal distribution within specific LNs on the basis of VJ usage. Together, these results suggest prolonged maintenance of naïve T cells through in situ homeostasis and retention in lymphoid tissue.

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