The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement
The germinal center (GC) is a hallmark microenvironment for the T-dependent antibody response, in which activated B cells divide, mutate their antigen receptor genes, compete for antigen, and are selected on the basis of high-affinity antigen binding in order to produce protective antibodies. GCs form in the center of the B cell follicle and GC B cells remain both spatially confined to their niche and segregated from naive B cells in the surrounding follicle. In addition, GC size is tightly controlled, and it is not understood whether the spatial organization and physical restrictions play a role in controlling GC B cell growth and homeostasis. We set out to identify cues involved in positioning GC B cells in the center of the follicle and contributing to their confinement within the GC.
Sphingosine-1-phosphate receptor-2 (S1P2)-deficient mice develop diffuse large B cell lymphoma. However, the role of S1P2 in normal 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.