Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-γ response

The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid SIP (sphingosine 1-phosphate), we found that cells sensed higher concentrations of SIP in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the SIP receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-gamma by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization and reveal a previously unknown role for SIP in positioning cells within the medulla.