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

对病原体的免疫防御主要是通过包括T细胞在内的一系列血细胞的活动来实现的。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制集中到活动部位。淋巴细胞极化的例子包括：(1)形成一个单一的突起或尾足，构成细胞与细胞相互作用的基础；(2)形成免疫突触，使T细胞能够识别病原体；(3)细胞杀伤机制朝向目标。细胞极化的过程在神经元和上皮细胞中表现得最好，这两者都是不对称的。在每种细胞类型中，调节极化的一个主要机制是表达和靶向一系列包含称为PDZ结构域的区域的蛋白质。PDZ结构域调节蛋白质之间的相互作用，因此允许组装大分子支架，这些支架将蛋白质固定在特定的细胞位置。一些细胞中细胞极性的丧失被认为是导致不受控制的增殖和肿瘤进展的原因，一些含有PDZ的蛋白质是肿瘤抑制因子。我们已经确定了一种在T细胞中极化的含有PDZ的蛋白，并有证据表明该蛋白与细胞表面受体相互作用并控制其极化，该受体的功能包括调节T细胞的功能和增殖。这项建议的目的是确定这两种蛋白质在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是否对T细胞增殖重要。

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.