LFA-1-MEDIATED COSTIMULATION

描述：抗原呈递给T细胞需要形成稳定的 T细胞和抗原提呈细胞(APC)之间的复合体。队形 这种复合体的性质和稳定性是由黏附分子控制的，大多数 尤其是LFA-1。这种复合体为细胞间和细胞内提供 蛋白质：T细胞所必需的蛋白质相互作用 激活。调查人员的初步结果显示，除了其 作为黏附分子，LFA-1可以作为共刺激分子发挥作用。 LFA-1对T细胞活化的这种功能作用可以通过 IL-2基因表达的诱导和继发性IL-4的下调 回应。此外，LFA-1的共同参与可以改变 募集到T细胞部位形成的黏附复合体的蛋白质：APC 互动。此应用程序的总体目标是确定 这些蛋白的募集，或LFA-1在指导 黏附复合体中蛋白质的组织，对 LFA-1的共刺激功能。他们将剖析不同的结构 CD18胞浆尾部通过多种途径赋予LFA-1多种功能的特征 定点突变和基因转移。通过分离特定的功能， 他们希望辨别粘附力的结构组织 复合体在LFA-1功能和T细胞活化中发挥不可或缺的作用 将军。他们将通过三个具体目标做到这一点： 目的1：确定介导T细胞的LFA-1的结构特征 共刺激效应。 目标2：确定LFA-1在T的结构组织中的作用 细胞：APC黏附复合体。 目的3：确定β1(VLA-4)和β2(LFA-1)整合素是否 在T细胞共刺激中功能相同。

DESCRIPTION: Antigen presentation to T cells requires the formation of a stable complex between the T cell and an antigen presenting cell (APC). The formation of and stability of this complex is controlled by adhesion molecules, most notably LFA-1. This complex provides for both intercellular and intracellular protein:protein interactions to take place that are essential to T cell activation. The investigators' preliminary results show that in addition to its role as an adhesion molecule, LFA-1 can function as a costimulatory molecule. This functional effect of LFA-1 on T cell activation can be detected by the induction of IL-2 gene expression and the down regulation of secondary IL-4 responses. In addition, co-engagement of LFA-1 can alter the composition of proteins recruited to the adhesion complex that forms at the site of T cell:APC interaction. The overall goal of this application is to determine whether the recruitment of these proteins, or the possible role of LFA-1 in directing the organization of proteins within the adhesion complex, impacts on the costimulatory function of LFA-1. They will dissect the distinct structural features of the CD18 cytosolic tail that impart various functions of LFA-1 by site directed mutagenesis and gene transfer. By segregating specific functions, they hope to discern whether the structural organization of the adhesion complex plays an integral role in LFA-1 function and in T-cell activation in general. They will do this through three Specific Aims: Aim 1: Determine the structural features of LFA-1 that mediate T cell costimulation. Aim 2: Determine the role of LFA-1 in the structural organization of the T cell:APC adhesion complex. Aim 3: Determine whether beta1 (VLA-4) and beta2 (LFA-1) integrins are functionally equivalent in T cell costimulation.