KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells.
KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells.
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DOI：
10.1371/journal.pone.0043859
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Conforti L
中科院分区：
文献类型：
--
作者：
Kuras Z;Yun YH;Chimote AA;Neumeier L;Conforti L
T淋巴细胞的迁移是适应性免疫应答的重要组成部分，因为T细胞在身体周围循环以进行免疫监视。在迁移过程中，T细胞贴壁，在细胞前部形成前缘，在细胞后部形成尾足。我们的兴趣是在研究参与的离子通道在活化的人T淋巴细胞的迁移，因为它们调节细胞内Ca 2+水平。Ca 2+是细胞运动的关键调节剂。为此目的，我们创建了由生物聚合物PNMP制成并涂覆有ICAM-1（LFA-1的配体）的蛋白质表面。LFA-1和ICAM-1相互作用促进T细胞从血液进入组织，并且在免疫监视和炎症中至关重要。激活的人类T淋巴细胞通过随机游走在ICAM-1表面上极化和迁移，平均速度为0.6 µm/min。共聚焦显微镜表明Kv1.3、CRAC和TRPM 4通道位于前沿，而KCa3.1和TRPM 7通道聚集在尾足中。KCa3.1和TRPM 7在尾足的定位与我们在该细胞室中测量的细胞内Ca 2+水平的振荡相关。针对Kv1.3（ShK）、KCa3.1（TRAM-34）、CRAC（SKF-96365）、TRPM 7（2-APB）和TRPM 4（格列本脲）的阻断剂的进一步研究表明，阻断KCa3.1和TRPM 7而非Kv1.3、CRAC或TRPM 4可抑制T细胞迁移。用针对TRPM 7的siRNA证实了TRPM 7参与细胞迁移。TRPM 7的下调显著降低了迁移T细胞的数量和迁移T细胞的平均速度。这些结果表明，KCa3.1和TRPM 7选择性地定位于迁移T淋巴细胞的尾足，是T细胞迁移机制的关键组成部分。
The migration of T lymphocytes is an essential part of the adaptive immune response as T cells circulate around the body to carry out immune surveillance. During the migration process T cells polarize, forming a leading edge at the cell front and a uropod at the cell rear. Our interest was in studying the involvement of ion channels in the migration of activated human T lymphocytes as they modulate intracellular Ca2+ levels. Ca2+ is a key regulator of cellular motility. To this purpose, we created protein surfaces made of the bio-polymer PNMP and coated with ICAM-1, ligand of LFA-1. The LFA-1 and ICAM-1 interaction facilitates T cell movement from blood into tissues and it is critical in immune surveillance and inflammation. Activated human T lymphocytes polarized and migrated on ICAM-1 surfaces by random walk with a mean velocity of ∼6 µm/min. Confocal microscopy indicated that Kv1.3, CRAC, and TRPM4 channels positioned in the leading-edge, whereas KCa3.1 and TRPM7 channels accumulated in the uropod. The localization of KCa3.1 and TRPM7 at the uropod was associated with oscillations in intracellular Ca2+ levels that we measured in this cell compartment. Further studies with blockers against Kv1.3 (ShK), KCa3.1 (TRAM-34), CRAC (SKF-96365), TRPM7 (2-APB), and TRPM4 (glibenclamide) indicated that blockade of KCa3.1 and TRPM7, and not Kv1.3, CRAC or TRPM4, inhibits the T cell migration. The involvement of TRPM7 in cell migration was confirmed with siRNAs against TRPM7. Downregulation of TRPM7 significantly reduced the number of migrating T cells and the mean velocity of the migrating T cells. These results indicate that KCa3.1 and TRPM7 selectively localize at the uropod of migrating T lymphocytes and are key components of the T cell migration machinery.
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