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EBI2 mediates B cell segregation between the outer and centre follicle

Nature volume 460, pages 1122–1126 (2009)Cite this article

Abstract

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.

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Figure 1: EBI2 upregulation in activated B cells and downregulation in germinal centres.
Figure 2: EBI2 promotes localization of activated B cells in the outer follicle.
Figure 3: EBI2-deficient B cells localize to the follicle centre in a LTα1β2- and CXCL13-dependent manner.
Figure 4: Maintained Ebi2 expression impairs participation in germinal centre response.

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Acknowledgements

We thank C. Allen for help with microscopy and discussions, J. Green, E. Gray and K. Suzuki for helpful advice and J. An for expert assistance with the mouse colony. We also thank N. Killen and J. Dietrich for help with gene targeting. J.P.P. is an Associate and J.G.C. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by grants from the National Institutes of Health.

Author Contributions J.P.P. and J.G.C. designed and conceptualized the research; J.P.P., L.M.K. and Y.X. performed the experiments. J.P.P., L.M.K. and J.G.C. analysed the data, prepared the figures and wrote the manuscript.

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  1. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143, USA,

    João P. Pereira, Lisa M. Kelly, Ying Xu & Jason G. Cyster

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  1. João P. Pereira
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  4. Jason G. Cyster
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Correspondence to Jason G. Cyster.

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Pereira, J., Kelly, L., Xu, Y. et al. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009). https://doi.org/10.1038/nature08226

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