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

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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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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