From Development to Aging: Dynamic Roles of the Thymic Medulla in T Cell Biology

ABSTRACT The thymic medulla is essential for establishing central tolerance, orchestrating the development of a diverse yet self‐tolerant T cell repertoire, and preventing autoimmunity. This process is primarily mediated through interactions between developing thymocytes and antigen‐presenting cells, including thymic epithelial cells (TECs) and dendritic cells (DCs), with additional regulatory contributions from endothelial cells, mesenchymal cells, and macrophages. Despite its critical role, the complexity of late‐stage thymocyte development and the dynamics of their medullary residency remain incompletely understood. Recent advances in single‐cell, epigenomic, and transcriptomic technologies have begun to reveal previously unappreciated layers of cellular and molecular heterogeneity within the thymic medulla throughout life. In this review, we explore how the medulla shapes the fate of both conventional and non‐conventional T cells, examine the diversity of thymocyte populations it supports, and discuss how this specialized microenvironment adapts during aging and regeneration.