Effectors, mechanisms and consequences of sphingomyelinase-dependent regulation of actin dynamics in measles virus induced T cell paralysis

T细胞麻痹是麻疹病毒（MV）诱导的免疫抑制的一个主要标志，这反映在对有丝分裂信号的增殖反应丧失上。在细胞水平上，这与其下游效应器的激活取消有关，包括那些调节肌动蛋白细胞骨架动力学的效应器。我们最近将T细胞的细胞骨架麻痹归因于细胞鞘磷脂酶（SMase）的激活和随后膜神经酰胺的积累，这反映了肌动蛋白基突起的丧失、肌动蛋白和受体的极化以及细胞骨架连接蛋白的激活，这是对MV糖蛋白复合物与一种未知受体相互作用的反应。目前的应用旨在1)鉴定MV引起T细胞瘫痪的受体及其与信号通路（包括SMase途径）的耦合特性，2)表征MV诱导神经酰胺积累的分子机制，并评估表面受体的侧向分离和肌动蛋白动态依赖运动及其调节的影响，最后，作为这些研究的后续研究，3)神经酰胺升高调节T细胞活化阈值水平的潜力。利用MV表面与T细胞的相互作用作为模型系统，这些研究将通过靶向肌动蛋白动态激活过程来强调受体依赖性SMase激活对调节T细胞反应的影响。

T cell paralysis is a major hallmark of measles virus (MV)-induced immunosuppression which is reflected by a loss of proliferative responses to mitogenic signals. At a cellular level, this has been related to abrogation of activation of its downstream effectors also including those regulating actin cytoskeletal dynamics. We have recently attributed T cell cytoskeletal paralysis as reflected by the loss of actin based protrusions, actin and receptor polarization, and activation of cytoskeletal linker proteins to activation of cellular sphingomyelinases (SMase) and subsequent accumulation of membrane ceramides in response to interaction of the MV glycoprotein complex with an as yet unknown receptor. The current application now aims on 1) identification of the receptor used by MV to cause T cell paralysis and characterization of its coupling to signaling also including SMase pathways, 2) characterizing the molecular mechanisms underlying MV-induced ceramide accumulation and evaluating consequences on lateral segregation of surface receptors, and actin dynamic dependent motility and its regulation, and lastly, as a follow up ot these studies, 3) the potential of ceramide elevation to regulate threshold levels of T cell activation. Using MV surface interaction with T cells as a model system, these studies will highlight the impact of receptor-dependent SMase activation on regulating T cell responses by targeting actin dynamic activation processes.