B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1α chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4

被引:91
作者
Guinamard, R
Signoret, N
Masamichi, I
Marsh, M
Kurosaki, T
Ravetch, JV
机构
[1] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA
[2] UCL, Dept Biochem, London WC1E 6BT, England
[3] UCL, MRC, Mol Cell Biol Lab, London WC1E 6BT, England
[4] Kansai Med Univ, Dept Mol Genet, Moriguchi, Osaka 570, Japan
关键词
chemokine; lymphocyte; migration; signaling; phospholipase C;
D O I
10.1084/jem.189.9.1461
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Ca(2+) 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.
引用
收藏
页码:1461 / 1466
页数:6
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