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


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.


  1. Liu, Y.-J., Oldfield, S. & MacLennan, I. C. M. Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones. Eur. J. Immunol. 18, 355–362 (1988).

    CAS  Article  Google Scholar 

  2. Cyster, J. G. & Goodnow, C. C. Antigen-induced exclusion from follicles and anergy are separate and complementary processes that influence peripheral B cell fate. Immunity 3, 691–701 (1995).

    CAS  Article  Google Scholar 

  3. Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).

    ADS  CAS  Article  Google Scholar 

  4. Cyster, J. G. Chemokines and cell migration in secondary lymphoid organs. Science 286, 2098–2102 (1999).

    CAS  Article  Google Scholar 

  5. Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).

    CAS  Article  Google Scholar 

  6. Goodnow, C. C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    ADS  CAS  Article  Google Scholar 

  7. Gunn, M. D. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J. Exp. Med. 189, 451–460 (1999).

    CAS  Article  Google Scholar 

  8. Förster, R. et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 99, 23–33 (1999).

    Article  Google Scholar 

  9. Basten, A. et al. Self tolerance in the B cell repertoire. Immunol. Rev. 122, 5–19 (1991).

    CAS  Article  Google Scholar 

  10. Luther, S. A., Tang, H. L., Hyman, P. L., Farr, A. G. & Cyster, J. G. Coexpression of the chemokines ELC and SLC by T zone stromal cells and deletion of the ELC gene in the plt/plt mouse. Proc. Natl Acad. Sci. USA 97, 12694–12699 (2000).

    ADS  CAS  Article  Google Scholar 

  11. Nakano, H. & Gunn, M. D. Gene duplications at the chemokine locus on mouse chromosome 4: multiple strain-specific haplotypes and the deletion of secondary lymphoid-organ chemokine and EBI-1 ligand chemokine genes in the plt mutation. J. Immunol. 166, 361–369 (2001).

    CAS  Article  Google Scholar 

  12. Vassileva, G. et al. The reduced expression of 6Ckine in the plt mouse results from the deletion of one of two 6Ckine genes. J. Exp. Med. 190, 1183–1188 (1999).

    CAS  Article  Google Scholar 

  13. Förster, R. et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).

    Article  Google Scholar 

  14. Ansel, K. M. et al. A chemokine driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    ADS  CAS  Article  Google Scholar 

  15. Ouyang, W. et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9, 745–755 (1998).

    CAS  Article  Google Scholar 

  16. Van Parijs, L., Refaeli, Y., Abbas, A. K. & Baltimore, D. Autoimmunity as a consequence of retrovirus-mediated expression of C- FLIP in lymphocytes. Immunity 11, 763–770 (1999).

    CAS  Article  Google Scholar 

  17. Randolph, D. A., Huang, G., Carruthers, C. J. L., Bromley, L. E. & Chaplin, D. D. Differential expression of CCR7 on Th1 and Th2 cells: Importance in control of T cell localization and delivery of help for antibody responses in vivo. Science 286, 2159–2162 (1999).

    CAS  Article  Google Scholar 

  18. Foxman, E. F., Kunkel, E. J. & Butcher, E. C. Integrating conflicting chemotactic signals. The role of memory in leukocyte navigation. J. Cell Biol. 147, 577–588 (1999).

    CAS  Article  Google Scholar 

  19. Ngo, V. N., Tang, H. L. & Cyster, J. G. Epstein–Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J. Exp. Med. 188, 181–191 (1998).

    CAS  Article  Google Scholar 

  20. Kellermann, S. A., Hudak, S., Oldham, E. R., Liu, Y. J. & McEvoy, L. M. The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3 beta are potent chemoattractants for in vitro- and in vivo-derived dendritic cells. J. Immunol. 162, 3859–3864 (1999).

    CAS  PubMed  Google Scholar 

  21. Cyster, J. G., Hartley, S. B. & Goodnow, C. C. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371, 389–395 (1994).

    ADS  CAS  Article  Google Scholar 

  22. Mandik-Nayak, L., Bui, A., Noorchashm, H., Eaton, A. & Erikson, J. Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T–B interface of the splenic follicle. J. Exp. Med. 186, 1257–1267 (1997).

    CAS  Article  Google Scholar 

  23. Iwasaki, A. & Kelsall, B. L. Localization of distinct Peyer's patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3α, MIP-3β, and secondary lymphoid organ chemokine. J. Exp. Med. 191, 1381–1394 (2000).

    CAS  Article  Google Scholar 

  24. Blelloch, R., Newman, C. & Kimble, J. Control of cell migration during Caenorhabditis elegans development. Curr. Opin. Cell Biol. 11, 608–613 (1999).

    CAS  Article  Google Scholar 

  25. Nakano, H. et al. Genetic defect in T lymphocyte-specific homing into peripheral lymph nodes. Eur. J. Immunol. 27, 215–221 (1997).

    CAS  Article  Google Scholar 

  26. Gunn, M. D. et al. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature 391, 799–803 (1998).

    ADS  CAS  Article  Google Scholar 

  27. Naviaux, R. K., Costanzi, E., Haas, M. & Verma, I. M. The pCL vector system: rapid production of helper-free, high-titer, recombinant retroviruses. J. Virol. 70, 5701–5705 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pear, W. S., Nolan, G. P., Scott, M. L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl Acad. Sci. USA 90, 8392–8396 (1993).

    ADS  CAS  Article  Google Scholar 

  29. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    CAS  Article  Google Scholar 

  30. Schmidt, K. N., Hsu, C. W., Griffin, C. T., Goodnow, C. C. & Cyster, J. G. Spontaneous follicular exclusion of SHP1-deficient B cells is conditional on the presence of competitor wild-type B cells. J. Exp. Med. 187, 929–937 (1998).

    CAS  Article  Google Scholar 

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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).

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