EBI2 mediates B cell segregation between the outer and centre follicle

• Published in: Nature (London) Vol. 460; no. 7259; pp. 1122 - 1126
• Main Authors: Cyster, Jason G, Kelly, Lisa M, Xu, Ying, Pereira, João P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 27.08.2009
• Subjects: Animal models in research; Animals; B cells; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Biological and medical sciences; Bone marrow; Cell adhesion & migration; Chemokine CXCL13 - metabolism; Epstein-Barr virus; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Gene Expression Regulation; Germinal Center - cytology; Germinal Center - immunology; Immunobiology; Immunohistochemistry; Immunology; Lymphocyte Activation; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Mice; Mice, Inbred C57BL; Microenvironments; Physiological aspects; Proteins; Receptors, G-Protein-Coupled - deficiency; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Rodents; Stem cells; Lymph node; Germinative center; B-Lymphocyte
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature08226

B cell follicles are specialized microenvironments that support events necessary for humoral immunity. 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 follicle. Subsequently, some cells move to the follicle centre, become germinal centre B cells and undergo antibody affinity maturation. 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), 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.