B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4.
B cell antigen receptor engagement inhibits stromal cell-derived factor (SDF)-1alpha chemotaxis and promotes protein kinase C (PKC)-induced internalization of CXCR4.
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B 细胞抗原受体结合抑制基质细胞衍生因子 (SDF)-1α 趋化性并促进蛋白激酶 C (PKC) 诱导的 CXCR4 内化。
DOI：
10.1084/jem.189.9.1461
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发表时间：
1999-05-03
期刊：
影响因子：
--
通讯作者：
Ravetch JV
中科院分区：
文献类型：
--
作者：
Guinamard R;Signoret N;Ishiai M;Marsh M;Kurosaki T;Ravetch JV
B淋巴细胞进入次级淋巴器官是发展免疫反应的关键步骤，为免疫反应谱系的形成、抗原诱导的激活和选择提供了场所。这些事件由通过B细胞抗原受体(BCR)产生的信号控制，并与B细胞对趋化因子梯度的反应的迁移特性的变化有关。趋化因子基质细胞衍生因子-1α被认为是这些过程中的驱动力之一，因为它产生于次级淋巴器官内，诱导B淋巴细胞迁移，并在BCR参与时停止。使用缺乏特定bcr偶联信号成分的B细胞，从基因上解剖了介导这种停滞的信号通路。Bcr对SDF1α趋化的抑制作用依赖于Syk、BLNK、btk和磷脂酶C(Plc)γ2，但不依赖于钙离子的动员，提示bcr的作用靶点是依赖于蛋白激酶C的底物。这个靶点被确定为SDF-1α受体CXCR4，它在bcr刺激下经历依赖于PKC的内化。CXCR4 COOH末端内化基序SSXXIL的突变导致B细胞在BCR结合时结构性地表达该受体。这些研究表明，bcr刺激导致抑制sdf-1α迁移的一个途径是通过依赖蛋白激酶C下调cxCR4。
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)-1α 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-1α chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)γ2 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-1α 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-1α migration is through PKC-dependent downregulation of CXCR4.