TNF receptor superfamily signaling in lymphoid organ development and endothelial cell responses

Members of the TNF Receptor Superfamily (TNFRSF) are expressed on a wide variety of cells and implicated in development of lymphoid organs, including secondary lymphoid organs (SLOs) like lymph nodes (LNs) and spleen, and tertiary lymphoid organs (TLOs) which can develop locally during chronic inflammation and cancer. In addition, TNFRSF members activate different intracellular signaling pathways, of which NF-κB signaling is among the best known. NF-κB signaling is associated with a range of cellular responses in many different cell types, including endothelial cells (ECs). This work provides novel insights into the role of TNFRSF members in lymphoid organ development and EC activation and function during immune-mediated inflammatory diseases (IMIDs) and cancer. The first part of this thesis expands the knowledge on TNFRSF member signaling in lymphoid organs by 1) providing an overview of TNFRSF member signaling in the main EC subsets found in lymphoid organs EC, 2) identifying transmembrane (tm)TNF as a regulator of splenic function, and 3) generating new data on the role of TNFR signaling in the B cell clusters and vasculature of the LN. The second part of this thesis solidifies the role of ECs as active participants in inflammation and cancer by 1) providing in-depth insights into the role of NF-κB as regulator EC activation during these pathologies and 2) identifying NF-κB inducing kinase (NIK) as a key orchestrator of EC responses. As NIK signaling in EC is restricted to pathological events it may hold promise as therapeutic target in IMIDs and cancer.