The sphingosine 1-phosphate receptor S1P maintains the homeostasis of germinal center B cells and promotes niche confinement

Sphingosine-1-phosphate receptor-2 (S1P2)-deficient mice develop diffuse large B cell lymphoma. However, the role of S1P2 in normal germinal center (GC) physiology is unknown. Here we show that S1P2-deficient GC B cells outgrow their wild-type counterparts in chronically-established GCs. We find that S1P2-, G12–G13- and p115RhoGEF-mediated antagonism of Akt regulates cell viability and is required for growth control in chronically proliferating GCs. We also find that S1P2 inhibits GC B cell responses to follicular chemoattractants and helps confine cells to the GC. Moreover, S1P2 overexpression promotes centering of activated B cells within the follicle. We suggest that by inhibiting Akt activation and migration, S1P2 helps restrict GC B cell survival and localization to an S1P-low niche at the follicle center. Germinal centers (GCs) are induced in response to T-dependent antigens and support events necessary for antibody affinity maturation1,2. They arise in the center of B cell follicles and grow from small numbers of starting B cells to a size of ~10,000 cells in a matter of days. Despite the rapid growth rate, GC size is tightly regulated, even in mesenteric lymph nodes (mLNs) and Peyer's Patches (PPs) where the responses are chronically stimulated by gut flora3. Apoptosis is an integral part of GC growth control as GC B cells are highly prone to Address correspondence to: J.G.C