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Lymph nodes (LNs) are strategically situated throughout the body at junctures of the blood vascular and lymphatic systems to direct immune responses against antigens draining from peripheral tissues. The current paradigm describes LN development as a programmed process that is governed through the interaction between mesenchymal lymphoid tissue organizer (LTo) cells and hematopoietic lymphoid tissue inducer (LTi) cells. Using cell-type-specific ablation of key molecules involved in lymphoid organogenesis, we found that initiation of LN development is dependent on LTi-cell-mediated activation of lymphatic endothelial cells (LECs) and that engagement of mesenchymal stromal cells is a succeeding event. LEC activation was mediated mainly by signaling through receptor activator of NF-κB (RANK) and the non-canonical NF-κB pathway and was steered by sphingosine-1-phosphate-receptor-dependent retention of LTi cells in the LN anlage. Finally, the finding that pharmacologically enforced interaction between LTi cells and LECs promotes ectopic LN formation underscores the central LTo function of LECs.
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•LTβR signals in mesenchymal LTo cells are not essential for LN organogenesis•RANK-mediated signaling in lymphatic endothelial cells (LECs) drives LN development•LECs control retention of LTi cells in embryonic LN anlagen•Enforced LTi cell retention in lymphatics induces formation of ectopic LNs
Lymph node (LN) formation is thought to rely mainly on interactions between mesenchymal lymphoid tissue organizer cells and lymphoid tissue inducer cells. Onder et al. now show that LN formation is governed by RANK-dependent activation of lymphatic endothelial cells that control retention of lymphoid tissue inducer cells in embryonic LN anlagen.