Embryonic lympho-epithelial cell interactions play an essential role in the establishment of adult T cell tolerance

Abstract Thymic seeding progenitors (TSP) colonize the embryonic thymus in two successive waves, with the first wave uniquely contributing to lymphoid tissue inducer and invariant γδ T cells that drive primordial medullary thymic epithelial cell (mTEC) maturation. Although recognized during thymic organogenesis, their long-term impact on T cell selection and immune tolerance remains unclear. We show that selective depletion of first-wave TSP alters thymic architecture and TEC composition. This results in reduced mTEC numbers, failure of medullary islets to expand and coalesce, altered dendritic cell composition, and delayed regulatory T cell development. Single-cell transcriptional analysis revealed a decrease in the most immature and expanding compartments and signs of accelerated maturation. It also revealed abnormal TEC differentiation trajectories, expansion of post-Aire and mimetic TEC subsets, and altered expression of tissue-restricted antigen-coding genes. Functionally, first-wave TSP depletion resulted in impaired thymic recovery after injury, and age-associated autoimmunity, with elevated anti-nuclear antibodies and lymphocytic infiltration in peripheral tissues. Thus, first-wave TSP imprint long-lasting control of thymic function and immune tolerance. One sentence summary Early embryonic thymic seeding progenitors program thymic epithelial maturation and regulatory T cell development, ensuring long-term immune tolerance and protection from age-associated autoimmunity.