Monocyte-derived S1P in the lymph node regulates immune responses

The lipid chemoattractant sphingosine 1-phosphate (S1P) guides cells from the low-S1P environment of tissues into the high-S1P environment of circulatory fluids(1). Notably, S1P directs T cell exit from lymph nodes (LN), where T cells are initially activated, into lymph, from which T cells reach blood and ultimately inflamed tissues(1). T cells follow S1P gradients primarily using S1P receptor 1 (S1PR1)(1). While recent work has described how S1P gradients are established at steady-state, little is known about S1P distribution in disease, or about how changing S1P levels may affect immune responses. Here, we find that S1P concentrations increase in LN during an immune response. Hematopoietic cells, including inflammatory monocytes (iMo), are an important source of this S1P, an unexpected finding as endothelial cells provide lymph S1P(1). iMo require the early activation marker CD69 to supply this S1P, in part because CD69 expression is associated with reduced levels of S1pr5. CD69 acts as a “stand-your-ground” signal, keeping immune cells at a site of inflammation by regulating both S1P receptors and S1P gradients. Finally, increased S1P prolongs T cell residence time in LN, and exacerbates the severity of experimental autoimmune encephalomyelitis. This finding suggests the hypothesis that LN residence time regulates T cell differentiation, and points to novel uses of drugs targeting S1P signaling.