EBV induced molecule-2 mediates B cell segregation between outer and center follicle

B cell follicles are specialized microenvironments that support events necessary for humoral immunity 1, 2, 3. Following antigen encounter, activated B cells initially seek T cell help at the follicle-T zone boundary and then move to interfollicular and T-zone distal (outer) regions of the follicle 4, 5, 6, 7, 8, 9, 10. Subsequently, some cells move to the follicle center, become germinal center (GC) B cells and undergo antibody affinity maturation 1, 2, 11. Although germinal ‘centers’ within follicles were described in 1885 12, the molecular cues mediating segregation of B cells between outer and center follicle have remained undefined. Here we establish a role for the orphan G-protein coupled receptor, Epstein Barr Virus-induced molecule-2 (EBI2) 13, in this process. EBI2 is expressed in mature B cells and increases in expression early after activation before being down-regulated in GC B cells. EBI2 deficiency led to a reduction in the early antibody response to a T-dependent antigen. EBI2-deficient B cells failed to move to the outer follicle at day 2 of activation and instead were found in the follicle center, whereas EBI2 over-expression was sufficient to promote B cell localization to the outer follicle. In mixed bone marrow chimeras, EBI2-deficient B cells phenocopied GC B cells in preferentially localizing to the follicle center. When down-regulation of EBI2 in wild-type B cells was antagonized, participation in the GC reaction was impaired. These studies identify an important role for EBI2 in promoting B cell localization in the outer follicle, and show that differential expression of this receptor helps position B cells appropriately for mounting T-dependent antibody responses.