UCSF

The immune system is organized to allow lymphocytes to survey for antigen and rapidly respond to an infection. B lymphocytes reside in B cell follicles and, upon exposure to antigen, rapidly migrate to interact with T cells, and then later go on to quickly produce protective antibodies and more slowly generate a memory response to prevent later reinfection. The role of chemokines and their receptors in positioning naïve and activated cells is well appreciated; CXCR5 is required for B cells to home to B cell follicles, and CCR7 is required for migration toward T cells. However, the positioning of B cells is not completely explained by these two chemokine receptors. During activation, B cells migrate after T cell interaction to the outer follicle, and some then migrate toward the center of the follicle to form germinal centers. The cues positioning cells to these areas have been poorly understood. Here we describe the role of the G protein coupled receptor EBI2 in positioning B cells, both homeostatically and upon activation. EBI2 promotes naïve B cell localization to the outer follicle, and EBI2 deficient cells are found toward the center of the follicle in competition. EBI2 expression is increased after B cell activation, directing activated cells to the outer follicle before CCR7 brings them toward T cells. After receiving CD40 stimulation from T cells, activated B cells migrate again to the outer follicle in an EBI2-dependent manner. EBI2 downregulation is required for B cells to move into the follicle and for germinal center development. Some cells remain at the outer follicle and produce antibody. EBI2 is required for efficient antibody production in a T-dependent immune response. These data demonstrate that EBI2 acts in coordination with the chemokine receptors CXCR5 and CCR7 to position naïve and activated B cells and contributes to the immune response.