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Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position

Nature volume 416, pages 94–99 (2002)Cite this article

Abstract

B lymphocytes re-circulate between B-cell-rich compartments (follicles or B zones) in secondary lymphoid organs, surveying for antigen. After antigen binding, B cells move to the boundary of B and T zones to interact with T-helper cells1,2,3. Despite the importance of B–T-cell interactions for the induction of antibody responses, the mechanism causing B-cell movement to the T zone has not been defined. Here we show that antigen-engaged B cells have increased expression of CCR7, the receptor for the T-zone chemokines4,5 CCL19 and CCL21, and that they exhibit increased responsiveness to both chemoattractants. In mice lacking lymphoid CCL19 and CCL21 chemokines, or with B cells that lack CCR7, antigen engagement fails to cause movement to the T zone. Using retroviral-mediated gene transfer we demonstrate that increased expression of CCR7 is sufficient to direct B cells to the T zone. Reciprocally, overexpression of CXCR5, the receptor for the B-zone chemokine CXCL13, is sufficient to overcome antigen-induced B-cell movement to the T zone. These findings define the mechanism of B-cell relocalization in response to antigen, and establish that cell position in vivo can be determined by the balance of responsiveness to chemoattractants made in separate but adjacent zones.

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Figure 1: Antigen-engaged B cells upregulate CCR7, increase responsiveness to T-zone chemokines and migrate to the outer T zone.
Figure 2: Localization of antigen-engaged B cells along the B/T boundary is dependent on both T- and B-zone chemokines.
Figure 3: Increased expression of CCR7 is sufficient to mediate B-cell redistribution to the T zone.
Figure 4: Overexpression of CXCR5 is sufficient to override antigen-induced B-cell movement to the T-cell zone.
Figure 5: Schematic representation of the mechanism for B-cell movement to the B/T boundary after BCR engagement.

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Acknowledgements

We thank K. Murphy and W. Sha for retroviral vectors; P. Andres, D. Bhattarcharya, Y. Refaeli and W. Sha for advice; M. Matloubian, T. Okada, D. Stainier and A. Weiss for comments on the manuscript; and A. Bidgol for help with screening mice. K.R. was supported by a Human Frontier Science Program Long Term Fellowship and is currently supported by a Leukemia and Lymphoma Society Special Fellowship. E.H.E. is a Howard Hughes Medical Institute (HHMI) predoctoral fellow, and J.G.C. is a HHMI assistant investigator and a Packard Fellow. This work was supported in part by a grant from the National Institutes of Health.

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Author notes

  1. Karin Reif, Eric H. Ekland and Martin Lipp: These authors contributed equally to this work

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, 94143-0414, California, USA

    Karin Reif, Eric H. Ekland & Jason G. Cyster

  2. University Clinic for Surgery, Nikolaus-Fiebiger-Center, Erlangen, 91054, Germany

    Lars Ohl & Reinhold Förster

  3. Department of Immunology, Toho University School of Medicine, Ota-Ku, 143-8540, Tokyo, Japan

    Hideki Nakano

  4. Molecular Tumorgenetics and Immunogenetics, Max-Delbrück-Center for Molecular Medicine, Berlin, 13092, Germany

    Martin Lipp

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Correspondence to Jason G. Cyster.

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Reif, K., Ekland, E., Ohl, L. et al. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416, 94–99 (2002). https://doi.org/10.1038/416094a

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