Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion
Tec kinases regulate TCR-mediated recruitment of signaling molecules and integrin-dependent cell adhesion
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DOI：
10.4049/jimmunol.175.9.5923
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Schwartzberg, PL
中科院分区：
文献类型：
--
作者：
Finkelstein, LD;Shimizu, Y;Schwartzberg, PL
Tee激酶Itk或Itk和Rlk缺陷的T细胞表现出TCR刺激的增殖、IL-2产生和磷脂酶C-γ活化缺陷。证据还表明，Tee激酶参与肌动蛋白细胞骨架调节，这是T淋巴细胞中细胞粘附和免疫突触形成所必需的。在这项研究中，我们表明，Tee激酶是TCR介导的上调粘附通过LFA-1整合素。我们还证明了粘附缺陷与LFA-1和talin在Rlk（-/-）Itk（-/-）和Itk（-/-）T细胞与抗TCR包被的珠粒相互作用位点的缺陷性聚集有关。在Rlk（-/-）Itk（-/-）和Itk（-/-）T细胞中也观察到Vav 1、蛋白激酶C θ和Pyk 2的募集缺陷。ICAM-2与抗TCR包被的珠子联合刺激增强了野生型细胞中Vav 1、蛋白激酶C θ和Pyk 2的极化，证明了整合素在增强T细胞中信号分子募集中的作用。在低TCR刺激的条件下，信号分子的募集增加最明显。在这些次优TCR刺激条件下，ICAM-2也可以增强Itk（-/-）T细胞中信号分子的募集，但不能增强Rlk（-/-）Itk（-/-）T细胞中信号分子的募集。因此，Tee激酶在调节TCR介导的整合素和信号传导分子向TCR刺激位点的极化以及整合素粘附的上调中起关键作用。
T cells deficient in the Tee kinases Itk or Itk and Rlk exhibit defective TCR-stimulated proliferation, IL-2 production, and activation of phospholipase C-gamma. Evidence also implicates Tee kinases in actin cytoskeleton regulation, which is necessary for cell adhesion and formation of the immune synapse in T lymphocytes. In this study we show that Tee kinases are required for TCR-mediated up-regulation of adhesion via the LFA-1 integrin. We also demonstrate that the defect in adhesion is associated with defective clustering of LFA-1 and talin at the site of interaction of Rlk(-/-)Itk(-/-) and Itk(-/-) T cells with anti-TCR-coated beads. Defective recruitment of Vav1, protein kinase C theta, and Pyk2 was also observed in Rlk(-/-)Itk(-/-) and Itk(-/-) T cells. Stimulation with ICAM-2 in conjunction with anti-TCR-coated beads enhanced polarization of Vav1, protein kinase C theta, and Pyk2 in wild-type cells, demonstrating a role for integrins in potentiating the recruitment of signaling molecules in T cells. Increased recruitment of signaling molecules was most pronounced under conditions of low TCR stimulation. Under these suboptimal TCR stimulation conditions, ICAM-2 could also enhance the recruitment of signaling molecules in Itk(-/-), but not Rlk(-/-)Itk(-/-) T cells. Thus, Tee kinases play key roles in regulating TCR-mediated polarization of integrins and signaling molecules to the site of TCR stimulation as well as the up-regulation of integrin adhesion.