Intrathymic SIRPa cDC subsets organization in normal and stress conditions reveal another level of cDCs heterogeneity

Three major subsets constitute the dendritic cells (DCs) pool in the thymus. They play key roles in self-antigen-specific thymocyte deletion and in the development of immunoregulatory T cells. Resident SIRPa^- conventional DCs (cDCs, CD11c⁺ PDCA1^lo ) are derived from intrathymic progenitors, whereas migratory SIRPa⁺ cDCs and plasmacytoid DCs (pDCs, CD11c⁺ PDCA1⁺ ) originate from extrathymic sites. Here, we describe the organization and the shaping of cDC populations at the steady state and under stress conditions in wild-type and mutant mice (CD3eKO, IL7RaKO, and Flt3LKO). In neonates, the thymus is mainly composed of SIRPa^- -resident cDCs, whereas both cDC subsets are present in equal proportions in the adult. Upon thymus colonization, migratory SIRPa⁺ cDCs gain expression of phenotypic markers in a microenvironment dependent way. Here, we show that both processes are deeply impacted by mutations affecting T cell development. Under stress conditions such as sublethal irradiation, intrathymic resident SIRPa^- cDCs are the first to regenerate the thymic cDC pool. Upon bone marrow transplantation, migratory SIRPa⁺ cDCs become the main source of thymic cDCs. These successive waves of regeneration eventually lead to a balance between resident and migratory DCs within the newly colonized thymus. These findings highlight an unrevealed division of labor between resident and migratory subsets for the organization/establishment of the thymic cDC compartment.