Lymph node medulla regulates the spatiotemporal unfolding of resident dendritic cell networks.

Unlike macrophage networks composed of long-lived tissue-resident cells within specific niches, conventional dendritic cells (cDCs) that generate a 3D network in lymph nodes (LNs) are short lived and continuously replaced by DC precursors (preDCs) from the bone marrow (BM). Here, we examined whether specific anatomical niches exist within which preDCs differentiate toward immature cDCs. In situ photoconversion and Prtn3 -based fate-tracking revealed that the LN medullary cords are preferential entry sites for preDCs, serving as specific differentiation niches. Repopulation and fate-tracking approaches demonstrated that the cDC1 network unfolded from the medulla along the vascular tree toward the paracortex. During inflammation, collective maturation and migration of resident cDC1s to the paracortex created discontinuity in the medullary cDC1 network and temporarily impaired responsiveness. The decrease in local cDC1 density resulted in higher Flt3L availability in the medullary niche, which accelerated cDC1 development to restore the network. Thus, the spatiotemporal development of the cDC1 network is locally regulated in dedicated LN niches via sensing of cDC1 densities. [Display omitted] • Resident and migratory cDC1s generate distinct networks in LNs • The LN medulla is a niche for DC precursor homing and differentiation • Prtn3 -based fate tracking reveals differentiation trajectories of preDCs in LNs • Local Flt3L-mediated feedback accelerates cDC1 development in the LN Conventional dendritic cells (cDCs) are short-lived cells, being constantly replaced by precursors (preDCs) from the bone marrow. Ugur et al. provide insight into the niches that maintain these cells, showing that preDCs home to the LN medulla and generate a network that extends toward the paracortex. Inflammation promotes rapid maturation of cDC1s, leaving gaps in this network that are filled by local Flt3L feedback. [ABSTRACT FROM AUTHOR]