The interaction between CD46 and PSD-95/Dlg-4: Roles in cell polarisation and CD46 signalling.

针对病原体的免疫防御主要通过一系列血细胞（包括T细胞）的活动来实现。T细胞具有特殊的功能，包括直接杀死病原体，以及招募和激活其他免疫细胞。这些功能中的许多需要淋巴细胞变得极化或不对称，以便将适当的细胞机器集中到活动部位。淋巴细胞中极化的实例包括（i）形成单个突起或尾足，其形成细胞-细胞相互作用的基础，（ii）形成允许T细胞识别病原体的免疫突触，以及（iii）将细胞杀伤机制导向靶。细胞极化的过程在神经元和上皮细胞中表现得最好，两者都是不对称的。在每种细胞类型中，调节极化的主要机制是表达和靶向含有称为PDZ结构域的区域的蛋白质家族。PDZ结构域介导蛋白质-蛋白质相互作用，因此允许将蛋白质保持在特定细胞位点的大分子支架的组装。一些细胞中细胞极性的丧失被认为会导致不受控制的增殖和肿瘤进展，而一些含PDZ的蛋白质是肿瘤抑制剂。我们已经鉴定了在T细胞中极化的含PDZ的蛋白质，并且有证据表明该蛋白质与细胞表面受体相互作用并控制其极化，所述细胞表面受体的功能包括调节T细胞功能和增殖。该提案的目的是确定这两种蛋白在T细胞中极化的机制和功能后果，并确定它们的相互作用或极化对T细胞增殖是否重要。

Immune defence against pathogens is primarily achieved by the activities of a range of blood cells, including T cells. T cells have specialised functions involving direct killing of the pathogen, and recruitment and activation of other immune cells. Many of these functions require the lymphocyte to become polarised, or asymmetric, in order to concentrate the appropriate cellular machinery towards the site of activity. Examples of polarisation in lymphocytes includes (i) the formation of a single protrusion, or uropod, that forms the basis for cell-cell interactions, (ii) the formation of an immune synapse which allows a T cell to recognise a pathogen, and (iii) the direction of the cellular killing machinery towards the target. The process of cell polarisation is best characterised in neurons and epithelial cells, both of which are asymmetric. In each cell type, a major mechanism of regulating polarisation is the expression and targeting of a family of proteins containing regions called PDZ domains. PDZ domains mediate protein-protein interactions and so allow the assembly of large molecular scaffolds which hold proteins in specific cell sites. The loss of cell polarity in some cells is thought to cause uncontrolled proliferation and tumour progression, and some of the PDZ-containing proteins are tumour suppressors. We have identified a PDZ-containing protein that is polarised in T cells, and have evidence that this protein interacts with and controls the polarisation of a cell surface receptor whose functions include the regulation of T cell function and proliferation. The aim of this proposal is to determine the mechanisms and functional consequences of polarisation of these two proteins in T cells, and to determine whether their interaction or polarisation is important for T cell proliferation.