Thymic pioneers: Charting the origin, identity, and fate of human thymus seeding progenitors

T cells develop in the specialized microenvironment of the thymus but originate from hematopoietic stem cells in the bone marrow. Particularly in human, the identity and characteristics of the precursor cells that travel through the circulation to seed the thymic tissue remains a matter of debate, and the hematopoietic lineage potential and eventual intrathymic differentiation trajectories have not been fully defined. In addition, the mechanisms regulating the homing and entry process in the thymus are largely unclear but may have critical translational implications for thymic rejuvenation and efficient T-cell generation in immunocompromised individuals. In this review, we discuss the current understanding of human thymus seeding progenitor biology, explore how the thymic microenvironment may contribute to diverging fates between different thymus seeding populations, and discuss relevant knowledge gaps that could guide further fundamental and applied research to harness the power of thymus seeding progenitors to advance human health.