Deconstructing the Thymic Microenvironment Through Genesis to Senescence

The thymus is essential for adaptive immunity, orchestrating the differentiation of hematopoietic progenitors into various T-cell lineages. Thymic epithelial cells (TECs) impart this unique function by mediating the major checkpoints in T-cell differentiation while also imposing stringent tolerance processes required to prevent autoimmunity. Achieving these feats requires extensive TEC specialization and the formation of distinct thymic microenvironments. These features change extensively throughout life, from the growth phases of the embryonic and perinatal thymus, into the steady-state adult, through responses to acute injury and regeneration and, finally, during age-related thymic involution. Here we review how hypothesis and technology have shaped the field's understanding of the thymic microenvironment. We focus on how the development of single-cell technologies has revealed a remarkably diverse cellular landscape shaped by progenitor cell differentiation, TEC proliferation, AIRE-mediated transcriptional processes, and the differentiation of thymic mimetic cell lineages.