Human Natural Killer Cells: Formation and Structure of Activating Synapses

描述(申请人提供)：自然杀伤细胞是先天免疫系统的一部分，是抵御病毒感染和肿瘤的主要防御系统。它们也可能在激活自身免疫性疾病方面发挥作用。它们通过形成激活的免疫突触来裂解目标，或者通过与这些细胞形成抑制性突触来抑制它们。这个项目的目标是了解免疫突触是如何形成的，以及它们是如何发挥作用的。这一知识可能有助于我们在可能需要的情况下增强(在病毒感染或肿瘤的情况下)或降低(在自身免疫性疾病的情况下)它们的细胞溶解活性。本研究的具体目的是通过以下几个方面来研究免疫突触的形成和功能：1.鉴定激活NK突触的外周超分子激活簇中肌动蛋白环的蛋白质组分以及这种多蛋白复合体的形成机制，特别是Wiscott-Aldrich综合征相互作用蛋白(WIP)及其磷酸化位点的作用。2.研究激活免疫突触形成的信号通路，特别是突触成分的磷酸化及其功能。3.明确肌球蛋白IIA和IIB在颗粒胞吐中的作用，颗粒胞吐是导致靶细胞溶解的最后一步。

DESCRIPTION (provided by applicant): Natural killer cells are part of the innate immune system, the primary defense against virus infections and tumors. They may also have a role in activating autoimmune diseases. They lyse their target through forming an activating immunological synapse or they are inhibited by forming an inhibitory synapse with these cells. The goal of this project is to understand how the immunological synapses are formed and how they function. This knowledge may help us to enhance (in the case of virus infection or tumors) or diminish (in the case of autoimmune diseases) their cytolytic activity in circumstances in which this may be desired. The Specific Aim of this proposal is to examine the formation and function of immunological synapses in human Natural Killer (NK) cells by: 1. Identifying the protein components of the actin ring in the peripheral supermolecular activation cluster of the activating NK synapse and the mechanism by which this multiprotein complex is formed, particularly the role of Wiscott-Aldrich Syndrome interacting protein (WIP) and its phosphorylation sites. 2. Studying the signaling pathways that lead to formation of the activating immunological synapse, particularly the phosphorylation of synaptic components and their functions. 3. Defining the role of Myosin IIA and IIB in granule exocytosis, the last step that leads to cytolysis of target cells.