Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eur J Immunol. 2012 Oct;42(10):2736-43. doi: 10.1002/eji.201142303. Epub 2012 Sep 10.
Rapid arrest of T cells at target sites upon engagement of chemokine receptors is crucial to the proper functioning of the immune system. Although T-cell arrest always occurs under hydrodynamic forces in vivo, most studies investigating the molecular mechanisms of arrest have been performed under static conditions. While the requirement of the adapter protein SLP-76 (Src homology 2-domain containing leukocyte-specific phosphoprotein of 76 kDa) in TCR-induced integrin activation has been demonstrated, its role in chemokine-triggered T-cell adhesion is unknown. Using a flow chamber system, we show that SLP-76 plays an important role in regulating the transition from tethering and rolling to firm adhesion of T cells under physiological shear flow in response to CXCL12α (stromal cell-derived factor-1α); SLP-76-deficient primary T cells exhibited defective adhesion with a significant decrease in the number of firmly arrested cells. We further demonstrate the N-terminal phosphotyrosines of SLP-76 play a critical role in T-cell adhesion under flow. These findings reveal a novel role for SLP-76 in CXCR4-mediated T lymphocyte trafficking.
T 细胞在趋化因子受体结合后迅速在靶位被捕获，这对免疫系统的正常功能至关重要。尽管 T 细胞在体内始终在流体动力作用下被捕获，但大多数研究趋化因子触发的 T 细胞黏附的分子机制的研究都是在静态条件下进行的。虽然已经证明衔接蛋白 SLP-76（Src 同源 2 结构域包含白细胞特异性磷酸蛋白 76kDa）在 TCR 诱导整合素激活中的作用，但它在趋化因子触发的 T 细胞黏附中的作用尚不清楚。我们使用流动室系统表明，SLP-76 在调节 T 细胞对 CXCL12α（基质细胞衍生因子-1α）的生理切变流反应中的从连接和滚动到牢固黏附的转换中起着重要作用；缺乏 SLP-76 的原代 T 细胞表现出黏附缺陷，牢固捕获的细胞数量显著减少。我们进一步证明 SLP-76 的 N 端磷酸酪氨酸在流动条件下的 T 细胞黏附中起着关键作用。这些发现揭示了 SLP-76 在 CXCR4 介导的 T 淋巴细胞转运中的新作用。
