Institute of Cellular and System Medicine, 'National' Health Research Institutes, Miaoli 350.
Department of Physiology and Biophysics, 'National' Defense Medical Center, Taipei 114.
J Mol Cell Biol. 2014 Dec;6(6):458-72. doi: 10.1093/jmcb/mju050. Epub 2014 Dec 29.
T-lymphocyte migration under flow is critical for immune responses, but the mechanisms by which flow modulates the migratory behaviors of T-lymphocytes remain unclear. Human peripheral blood T-lymphocytes (PBTLs), when stimulated with phorbol 12-myristate 13-acetate (PMA), stretched their cell bodies dramatically and moved along the flow direction. In contrast, stromal cell-derived factor-1α-stimulated PBTLs deformed and migrated in a random manner. Here we elucidated the molecular mechanisms underlying flow-induced directionality and deformation of PMA-stimulated PBTLs. PMA primed PBTLs for polarization under flow, with protein kinase C (PKC)-δ enriched in the leading edge, PKC-βI in the microtubule organizing center, and PKC-βII in the uropod and peripheral region. PKC-δ regulated cell protrusions in the leading edge through Tiam1/Rac1/calmodulin, whereas PKC-β regulated RhoA/Rho-associated kinase activity and microtubule stability to modulate uropod contractility and detachment. Our findings indicate that PKC-δ and -β coordinate in the cell leading edge and uropod, respectively, to modulate the directionality and deformability of migratory T-lymphocytes under flow.
T 淋巴细胞在流动状态下的迁移对于免疫反应至关重要，但是流动如何调节 T 淋巴细胞的迁移行为的机制尚不清楚。当用佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）刺激人外周血 T 淋巴细胞（PBTL）时，它们的细胞体显著伸展并沿流动方向移动。相比之下，基质细胞衍生因子-1α刺激的 PBTL 则以随机方式变形和迁移。在这里，我们阐明了 PMA 刺激的 PBTL 流动诱导的方向性和变形的分子机制。PMA 在流动下使 PBTL 极化，PKC-δ 在前沿富集，PKC-βI 在微管组织中心，PKC-βII 在尾足和外周区域。PKC-δ 通过 Tiam1/Rac1/钙调蛋白调节前沿中的细胞突出，而 PKC-β 调节 RhoA/Rho 相关激酶活性和微管稳定性，从而调节尾足的收缩和脱离。我们的研究结果表明，PKC-δ 和 -β 在细胞前沿和尾足分别协调，以调节流动状态下迁移 T 淋巴细胞的方向性和变形性。
