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特征，表现为对有丝分裂信号的增殖反应丧失。在细胞水平上，这与其下游效应器的激活有关，也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，反应是MV糖蛋白复合体与一种未知受体的相互作用。T细胞骨架瘫痪表现为基于肌动蛋白的突起的丧失、肌动蛋白和受体极化以及细胞骨架连接蛋白的激活。目前的应用主要集中在：1)MV引起T细胞瘫痪的受体的鉴定及其与信号通路的偶联；2)MV诱导神经酰胺堆积的分子机制及其对表面受体横向分离的影响；肌动蛋白的动态依赖运动及其调控；3)神经酰胺升高调节T细胞激活阈值水平的可能性。利用MV表面与T细胞的相互作用作为模型系统，这些研究将突出受体依赖的sMase激活通过靶向肌动蛋白动态激活过程来调节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.