EBI2 mediates B cell segregation between the outer and centre follicle

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Abstract
The correct positioning of B cells within lymphoid follicles is critical for mounting antibody responses, and positioning of activated B cells in interfollicular regions and in the outer follicle is also thought to be important for supporting normal interactions between T cells and B cells and normal B-cell proliferation. The molecular cues controlling these positioning events have been unknown. Pereira et al. now establish that EBI2, an orphan G-protein-coupled receptor upregulated by Epstein–Barr virus infection, promotes B-cell positioning in the outer follicle. By down-regulating EBI2, germinal centre B cells are able to move to the follicle centre. Mice lacking or mis-expressing this receptor are shown to mount defective antibody responses. B cells migrate to the outer or centre lymphoid follicle at different stages of antibody responses. Here it is shown that activated B cells must downregulate the orphan G protein-coupled receptor EBI2 to migrate to the centre follicles, where they mount T dependent antibody responses and establish germinal centres. B cell follicles are specialized microenvironments that support events necessary for humoral immunity1,2,3. After 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 follicle4,5,6,7,8,9,10. Subsequently, some cells move to the follicle centre, become germinal centre B cells and undergo antibody affinity maturation1,2,11. Although germinal centres within follicles were described in 1885 (ref. 12), the molecular cues mediating segregation of B cells between the outer and centre follicle have remained undefined. Here we present a role for the orphan G-protein-coupled receptor, Epstein-Barr virus induced molecule-2 (EBI2, also known as GPR183)13, in this process. EBI2 is expressed in mature B cells and increases in expression early after activation, before being downregulated in germinal centre B cells. EBI2 deficiency in mice 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 centre, whereas EBI2 overexpression was sufficient to promote B cell localization to the outer follicle. In mixed bone marrow chimaeras, EBI2-deficient B cells phenocopied germinal centre B cells in preferentially localizing to the follicle centre. When downregulation of EBI2 in wild-type B cells was antagonized, participation in the germinal centre 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.