Lymph node CD169 + sinusoidal macrophages are sentinel cells that recognize the danger signals and initiate the protective immune responses. However, the signals and the mechanism underlying their formation are not well known. During my thesis, I have shown that the cytokine Receptor Activator of NF-kB Ligand (RANKL) is required for their differentiation, starting from the embryogenesis up to four weeks after birth. The lymphatic endothelial cells (LECs) activated by RANKL expressed by mesenchymal cells form the niches for the primary differentiation of these macrophages. Yet, in adults, RANKL-activated LECs are required for their niche replenishment after transient depletion induced by an inflammatory stimulus. Beyond lymph node, my research has revealed a general requirement of the double signal RANKL & lymphotoxin LTα1β2 for the differentiation of non-osteoclastic CD169 + macrophages of spleen and bone marrow.