Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells
Rho kinase promotes alloimmune responses by regulating the proliferation and structure of T cells
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DOI：
10.4049/jimmunol.171.1.96
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发表时间：
2003-07-01
影响因子：
4.4
通讯作者：
Coffman, TM
中科院分区：
文献类型：
--
作者：
Tharaux, PL;Bukoski, RC;Coffman, TM
肌动蛋白-肌球蛋白细胞骨架的协调重排促进了T细胞激活和信号转导的早期和晚期事件。由于细胞形状重排的许多重要特征涉及小gtp结合蛋白，我们研究了Rho激酶对成熟T细胞功能的贡献。Rho激酶途径的抑制剂都具有类似的抑制原代淋巴细胞增殖的作用。同样，转染具有Rho激酶显性阴性、激酶缺陷突变体的人Jurkat T细胞系可减少Jurkat细胞的增殖。此外，Rho激酶的抑制显著减弱了T细胞活化的细胞因子基因表达程序，阻断了肌动球蛋白的聚合，并阻止了与脂筏共定位的TCR/CD3复合物的聚集。这些作用与体内的免疫反应有关，因为Rho激酶抑制剂显著延长了小鼠完全异体心脏移植的存活时间，并降低了细胞因子mrna的表达。因此，通过Rho激酶作用的Rho gtpase在细胞免疫应答过程中通过促进对T细胞信号传导至关重要的结构重排在T细胞活化中发挥独特作用。
Coordinated rearrangements of the actin-myosin cytoskeleton facilitate early and late events in T cell activation and signal transduction. As many important features of cell shape rearrangement involve small GTP-binding proteins, we examined the contribution of Rho kinase to the functions of mature T cells. Inhibitors of the Rho kinase pathway all had similar actions to inhibit the proliferation of primary lymphocyte cultures. Likewise, transfection of the human Jurkat T cell line with a dominant negative, kinase-defective mutant of Rho kinase diminished Jurkat cell proliferation. Furthermore, inhibition of Rho kinase substantially attenuated the program of cytokine gene expression that characterizes T cell activation, blocked actomyosin polymerization, and prevented aggregation of the TCR/CD3 complex colocalized with lipid rafts. These actions are relevant to immune responses in vivo, as treatment with a Rho kinase inhibitor considerably prolonged the survival of fully allogeneic heart transplants in mice and diminished intragraft expression of cytokine mRNAs. Thus, Rho GTPases acting through Rho kinase play a unique role in T cell activation during cellular immune responses by promoting structural rearrangements that are critical for T cell signaling.