Janik Riese, Annabel Kleinwort, Maurice Hannemann, Celine Hähnel, Stephan Kersting, Tobias Schulze

• B‐1 cells are crucially involved in immune defense and regulation of inflammation and autoimmunity. B‐1 cells are predominantly located in the peritoneal and pleural cavities, although body cavity B‐1 cells recirculate systemically under steady‐state conditions. The chemokines CXCL12 and CXCL13 have been identified as the main regulators of peritoneal B‐cell trafficking. In mice deficient for sphingosine‐1‐phosphate receptor 4 (S1PR4), B‐1a and B‐1b cell numbers are reduced in the peritoneal cavity by an unknown mechanism. In this study, we show that S1PR4‐mediated S1P signaling modifies the chemotactic response of peritoneal B cells to CXCL13 and CXCL12 in vitro. In vivo, S1PR4‐mediated S1P signaling affects both immigration into and emigration from the peritoneal cavity. Long‐term reconstitution experiments of scid mice with wt or s1pr4–/– peritoneal B cells revealed a distinct distributional pattern in secondary lymphoid organs. As a functional consequence, both plasmatic and mucosal IgM levels, the main product of B‐1a cells, are reduced in mice reconstituted with s1pr4–/– peritoneal cells. In summary, our data identify S1PR4 as the second S1P receptor (besides S1PR1), which is critically involved in the regulation of peritoneal B‐1 cell function.