Thymic Dendritic Cells Revisited

Central tolerance in the thymus ensures that the developing T cell repertoire is safe yet effective against infections. This process relies greatly on antigen presentation by both stromal and hematopoietic antigen-presenting cells (APCs), with dendritic cells (DCs) playing a particularly critical role. Thymic DCs acquire a broad spectrum of self-antigens, including tissue-restricted antigens (TRAs), inflammation-associated antigens (ISAs), and peripheral antigens imported via circulation or immigrating DCs. These diverse inputs allow DCs to mediate clonal deletion, regulatory T cell (Treg) induction, and other agonist selection outcomes. In this review, we revisit thymic DCs, outlining their ontogeny, transcriptional control, and functional specialization. We compare thymic DC1 and DC2 subsets with their peripheral counterparts, highlighting their distinct localizations, maturation cues, and division of labor: DC1 excel in cross-presentation and Treg generation, while DC2 preferentially drive clonal deletion. We also highlight the heterogeneity of DC2s, which consist of four distinct subsets based on their transcriptional and phenotypic programs. We further examine plasmacytoid DCs, transitional DCs, monocytes, and macrophages, which contribute to tolerance through apoptotic cell clearance, antigen transfer, and lineage diversion of thymocytes. Finally, we discuss the role of homeostatic maturation, sterile inflammatory cues, and thymic immigration in shaping APC diversity. Together, these insights underscore the heterogeneity of thymic APCs, the complexity of thymic DC biology, and its vital importance in enforcing immune self-tolerance.