The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/5/1461/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 9, May 3, 1999 1461-1466

Articles

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

Rodolphe Guinamard*, Nathalie Signoret{ddagger}, Masamichi Ishiai§, Mark Marsh{ddagger}, Tomohiro Kurosaki§, and Jeffrey V. Ravetch*

From the * Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York 10021; the {ddagger} 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)-1{alpha} 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-1{alpha} 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-1{alpha} 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-1{alpha} migration is through PKC-dependent downregulation of CXCR4.

Key Words: chemokine • lymphocyte • migration • signaling • phospholipase C

Address correspondence to Jeffrey V. Ravetch, Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: 212-327-7321; Fax: 212-327-7319; E-mail: ravetch{at}rockvax.rockefeller.edu

Abbreviations used: BLR1, Burkitt's lymphoma receptor 1; GCs, germinal centers; HSA, human serum albumin; PKC, protein kinase C; Plc, phospholipase C; wt, wild type.


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