Dendritic Cell Motility and T Cell Activation Requires Regulation of Rho-Cofilin Signaling by the Rho-GTPase Activating Protein Myosin IXb
Dendritic Cell Motility and T Cell Activation Requires Regulation of Rho-Cofilin Signaling by the Rho-GTPase Activating Protein Myosin IXb
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DOI：
10.4049/jimmunol.1300695
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发表时间：
2014-04-15
影响因子：
4.4
通讯作者：
Grabbe, Stephan
中科院分区：
文献类型：
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作者：
Xu, Yan;Pektor, Stefanie;Grabbe, Stephan
受刺激的树突状细胞（dc）定向迁移到次级淋巴器官并与ag特异性T细胞相互作用是诱导原发性免疫反应的先决条件。在这篇文章中，我们发现缺乏肌球蛋白IXB （Myo9b）的小鼠dc表现出Rho信号活性和下游肌动球蛋白收缩性的增加，以及Rho靶蛋白cofilin（一种肌动蛋白解聚合因子）的失活。在功能水平上，Myo9b(-/-) dc在体内和体外均表现出定向迁移活性受损。此外，尽管没有改变Ag的呈递和共刺激能力，Myo9b(-/-) dc在体外三维胶原基质和体内都是较差的T细胞刺激剂，这与DC-T细胞接触动力学和T细胞极化的改变有关。因此，Myo9b（-/-）小鼠在接触性超敏反应模型中表现出减弱的耳肿胀反应。Myo9b(-/-) dc的迁移和T细胞刺激能力受损在很大程度上是通过cofilin的药理激活恢复的。综上所述，这些结果表明Myo9b是dc中Rho/RhoA效应物Rho-kinase (Rho-associated coil- coil-forming kinase， ROCK) /LIM结构域激酶信号通路的负关键调控因子，控制cofilin失活和myosin II激活，因此可能在一定程度上控制适应性免疫反应的诱导。
Directed migration of stimulated dendritic cells (DCs) to secondary lymphoid organs and their interaction with Ag-specific T cells is a prerequisite for the induction of primary immune responses. In this article, we show that murine DCs that lack myosin IXB (Myo9b), a motorized negative regulator of RhoA signaling, exhibit increased Rho signaling activity and downstream actomyosin contractility, and inactivation of the Rho target protein cofilin, an actin-depolymerizing factor. On a functional level, Myo9b(-/-) DCs showed impaired directed migratory activity both in vitro and in vivo. Moreover, despite unaltered Ag presentation and costimulatory capabilities, Myo9b(-/-) DCs were poor T cell stimulators in vitro in a three-dimensional collagen matrix and in vivo, associated with altered DC-T cell contact dynamics and T cell polarization. Accordingly, Myo9b(-/-) mice showed an attenuated ear-swelling response in a model of contact hypersensitivity. The impaired migratory and T cell stimulatory capacity of Myo9b(-/-) DCs was restored in large part by pharmacological activation of cofilin. Taken together, these results identify Myo9b as a negative key regulator of the Rho/RhoA effector Rho-kinase [Rho-associated coiled-coil-forming kinase (ROCK)]/LIM domain kinase signaling pathway in DCs, which controls cofilin inactivation and myosin II activation and, therefore may control, in part, the induction of adaptive immune responses.