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J. Exp. Med., Volume 189, Number 9, May 3, 1999 1461-1466

B Cell Antigen Receptor Engagement Inhibits Stromal Cell-derived Factor (SDF)-1alpha Chemotaxis and Promotes Protein Kinase C (PKC)-induced Internalization of CXCR4

By Rodolphe Guinamard,* Nathalie Signoret,Dagger Masamichi Ishiai ,§ Mark Marsh,Dagger Tomohiro Kurosaki,§ and Jeffrey V. Ravetch*

From the * Laboratory of Molecular Genetics and Immunology,  The Rockefeller University, New York 10021; the Dagger  Medical Research Council Laboratory for Molecular Cell Biology and Department of Biochemistry, University College London, London WC1E 6BT, United Kingdom; and the § Department of Molecular Genetics, Kansai Medical University, Moriguchi, Osaka 570, Japan

The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell-derived factor (SDF)-1alpha is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1alpha chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)gamma 2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1alpha receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1alpha migration is through PKC-dependent downregulation of CXCR4.

Key words: chemokine;  lymphocyte;  migration;  signaling;  phospholipase C


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