Summary Plasma sphingosine-1-phosphate (S1P) regulates vascular permeability, and plasma and lymph S1P guide lymphocyte egress from lymphoid organs. S1P is made intracellularly, and little is known about how S1P is delivered into circulatory fluids. Here we find that mice without the major facilitator superfamily transporter Spns2 have a profound reduction in lymph S1P, but only a minor decrease in plasma S1P. Spns2-deficient mice have a redistribution of lymphocytes from the spleen to lymph nodes and a loss of circulating lymphocytes, consistent with normal egress from the spleen directed by plasma S1P and blocked egress from lymph nodes directed by lymph S1P. Spns2 is needed in endothelial cells to supply lymph S1P and support lymphocyte circulation. As the first differential requirement for lymph and blood S1P to our knowledge, Spns2 may be an attractive target for immune suppressive drugs.

Lipid phosphate phosphatase 3 in endothelial and epithelial cells promotes efficient T cell emigration from the thymus to the periphery.

The lymph node periphery is an important site for many immune functions, from pathogen containment to T helper differentiation, yet the cues that position cells in this region are largely undefined. Here, using a sphingosine 1-phosphate (S1P) reporter, we found that cells sensed higher concentrations of S1P in the medullary cords than in the T zone, and 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, S1P receptor 5 on NK cells, and CXCR4 were all required for NK cell localization during homeostasis and rapid interferon-γ production by NK cells after challenge. Our findings elucidate the spatial cues for NK cell organization, and reveal a novel role of S1P in positioning cells within the medulla.

Despite the importance of signaling lipids, many questions remain about their function because we have few tools to chart lipid gradients in vivo. Here we describe a sphingosine 1-phosphate (S1P) reporter mouse, and use this mouse to define S1P distribution in the spleen. Surprisingly, the presence of blood does not predict the concentration of signaling-available S1P. Large areas of the red pulp are S1P-low, while S1P can be sensed by cells inside the white pulp near the marginal sinus. Lipid phosphate phosphatase 3 maintains low S1P concentrations in the spleen, and enables efficient marginal zone B cell shuttling. The exquisitely tight regulation of S1P availability may explain how a single lipid can simultaneously orchestrate many immune cell movements.

Sepsis is a potentially life-threatening complication of an infection. Sepsis is mostly the consequence of systemic bacterial infections leading to exacerbated activation of immune cells by bacterial products, resulting in enhanced release of inflammatory mediators. Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, is a critical factor in the pathogenesis of sepsis, which is sensed by Toll-like receptor 4 (TLR4). The scientific community highly pursues the development of antagonists capable of blocking the cytokine storm by blocking TLR4. We report here that a recombinant molecule of 14.5 kDa belonging to the Fasciola hepatica fatty acid binding protein (Fh15) is capable of significantly suppressing the LPS-induced cytokine storm in a mouse model of septic shock when administered by the intraperitoneal route 1 h after a lethal LPS injection. These results suggest that Fh15 is an excellent candidate for drug development against endotoxemia.