Dendritic cell navigation in lymphoid organs

• Applicant: Professor Dr. Wolfgang Kastenmüller
• Subject Area: Immunology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529931558

Conventional dendritic cells (cDC) bridge the innate and adaptive immune system . There are two major subsets of cDC – cDC1, which are specialized in activating CD8 T cells, and cDC2, whose predominant feature is to stimulate CD4 T cells. Both subsets develop from precursors (preDC) that continuously exit the bone marrow (BM) and seed tissues. In draining lymph nodes (LNs), tissue-derived migratory cDC1 and cDC2 coalesce with distinct populations of LN-resident cDC1 and cDC2, which reach the LN as preDC via the blood and establish a complex 3D network of immune sentinels. Previous studies found that different cDC subsets preferentially localize within distinct topographic niches – namely cDC1 in the paracortex and cDC2 in the interfollicular zone and medulla. Conceptually, the question of how the cDC network is generated and maintained is particularly interesting given the fact that its cellular elements are continuously replaced as a result of the short half-life of cDC (days). Additionally, the network itself is highly dynamic due to the continuous migration of its cellular elements. This is in stark contrast to the extensively studied macrophage networks, which are composed of long-lived tissue resident cells that settle within specific niches that provide local survival and differentiation signals. Open Questions The development of preDC in the BM and the maturation of cDC in the steady state and after inflammation have been extensively studied in recent years. By contrast, the local development of preDC towards immature DC in lymphoid organs and the potential microanatomical niches in which this development might take place are largely unexplored. The current view is that preDC enter e.g. the LN via paracortical high endothelial venules (HEV), randomly integrate into the network and develop into immature DC – a model that does not involve specific topographic niches. In our preliminary data, however, we found that preDC to cDC development in LNs is orchestrated within a distinct microanatomical niche – the LN medulla (unpublished). This niche guides the spatiotemporal unfolding of a dynamic cDC network in a conveyor belt-like sequence that starts in the medulla and extends to the paracortex. However, several important questions remain to be addressed: Which stromal cells and subsets support the unfolding and the maintenance of immature and mature cDC networks? Which molecular mechanisms regulate the maintenance and local development of cDC networks in lymphoid organs? Does this crosstalk between stromal cells and cDC represent two-cell circuits in which each partner benefits from the other, similarly to the macrophage niche concept? In Pathfinder, we will address whether BM-derived preDC develop into immature DC using dedicated LN, thymic and splenic niches and how cDC generate and maintain a 3D network in lymphoid tissues that allows them to respond to homeostatic signals or infections on functional, spatial, and temporal levels.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Marc Bajénoff, Ph.D.