Thymic DC2 are heterogenous and include a novel population of transitional dendritic cells 3216

Description Myeloid cells, including dendritic cells (DCs) and macrophages, are essential for establishing central tolerance in the thymus by promoting T cell clonal deletion and regulatory T cell (Treg) generation. Previous studies suggest that the thymic DC pool consists of plasmacytoid DC (pDC), XCR1+ DC1 and SIRPa+ DC2. Yet the precise origin, development, and homeostasis, particularly of DC2, remain unresolved. Using single-cell transcriptomics and lineage-defining mouse models we identify nine major populations of thymic myeloid cells and describe their lineage identities. We show that thymus SIRPa+ DC population contain subsets of monocyte-derived cells–DCs (moDC), and monocyte derived macrophages (moMac), that are dependent on thymic interferons (IFNs). We further demonstrate that conventional DC2 undergo intrathymic maturation regulated by CD40 signaling. Finally, we identify a novel thymic population of CX3CR1+ transitional DC (tDC) amongst SIRPa+ DC that represent transedothelial DCs positioned near thymic microvessels enabling presentation of blood-born antigens in the thymus. Together, these finding reveal the thymus as a niche for diverse, developmentally distinct myeloid cells and elucidate their specific requirements for development and maturation.