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Conrad C. Bleul^*, Joachim L. Schultze, and Timothy A. Springer^*

From ^* The Center for Blood Research and Harvard Medical School, Department of Pathology, Boston, Massachusetts 02115; and the Department of Adult Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115

Migration of mature B lymphocytes within secondary lymphoid organs and recirculation between these sites are thought to allow B cells to obtain T cell help, to undergo somatic hypermutation, to differentiate into effector cells, and to home to sites of antibody production. The mechanisms that direct migration of B lymphocytes are unknown, but there is evidence that G protein–coupled receptors, and possibly chemokine receptors, may be involved. Stromal cell– derived factor (SDF)-1 is a CXC chemokine previously characterized as an efficacious chemoattractant for T lymphocytes and monocytes in peripheral blood. Here we show with purified tonsillar B cells that SDF-1 also attracts naive and memory, but not germinal center (GC) B lymphocytes. Furthermore, GC B cells could be converted to respond to SDF-1 by in vitro differentiation into memory B lymphocytes. Conversely, the migratory response in naive and memory B cells was significantly reduced after B cell receptor engagement and CD40 signaling. The receptor for SDF-1, CXC chemokine receptor 4 (CXCR4), was found to be expressed on responsive as well as unresponsive B cell subsets, but was more rapidly downregulated on responsive cells by ligand. Finally, messenger RNA for SDF-1 was detected by in situ hybridization in a layer of cells surrounding the GC. These findings show that responsiveness to the chemoattractant SDF-1 is regulated during B lymphocyte activation, and correlates with positioning of B lymphocytes within a secondary lymphoid organ.

C.C. Bleul was supported by a fellowship of the Deutsche Forschungsgemeinschaft, J.L. Schultze is a fellow of the Lymphoma Research Foundation of America. This work was supported by grant HL48675 of the National Institutes of Health.

Address correspondence to Timothy A. Springer, The Center for Blood Research and Harvard Medical School, Department of Pathology, 200 Longwood Ave., Boston, MA 02115. Phone: 617-278-3200; Fax: 617-278-3232; E-mail: springer{at}sprsgi.med.harvard.edu

¹ Abbreviations used in this paper: BCR, B cell receptor; BLR1, Burkitt's lymphoma receptor 1; DIG, digxigenin; F-actin, filamentous actin; GC, germinal center; IP10, interferon-inducible protein 10; L, ligand; Mig, monokine-induced by IFN-; MIP, macrophage inflammatory protein; mRNA, messenger RNA; SDF, stromal cell–derived factor; SSC, standard saline citrate; t, transfected.

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