CELL BIOLOGY OF IMMUNE INTERACTIONS

抗原（Ag）特异性T细胞与 抗原呈递细胞（APC）可以触发生产性免疫， 免疫反应或免疫反应中止。 这些不同的生物学结果 是由传递的信号的复杂积分决定的 当T细胞膜上的多个受体与 APC细胞膜上的反受体。 发现复杂 整合的细胞和分子机制，决定了 相互作用的细胞，是这些研究的长期目标。 使用新的3-D数字成像的T-APC结合物，最近显示， 信号和粘附蛋白被募集到细胞接触点 并形成空间分离的超分子活化簇（SMAC）。 该应用程序高度集中在结构和功能的 c-SMAC，其是TCR接合和活化的位点。 中央 该提议的前提是TCR相关的激活事件是 在新发现的c-SMAC中进行时空协调。 到 为了验证这一假设，我们将联合收割机结合使用T细胞转基因小鼠和 多维成像，并将定义4维分子 四个关键激活受体的易位和关联， c-SMAC：T-APC相互作用期间的TCR、CD 45、CD 4和CD 28。 这些研究 随后将进行衍生实验，以确定 这些受体中的每一种与c-SMAC的结合及其 生理意义 具体目标是：目标1。 以确定 c-SMAC在时间和三维分子组成上的精确性 TCR转基因小鼠的T细胞与B-APC之间形成的细胞缀合物。 目标2. 为了研究引起瞬时共定位的机制， CD 45与Ag结合的TCR和Lck在早期c-SMAC中的表达，并评估 这些易位的功能意义。 目标3。 研究 机制，导致短暂的早期协会的CD 4与 使用TCR和CD 4无尾转基因， 小鼠 目标4。 研究负责联系的机制， CD 28与cSMAC中的接合TCR以及c-SMAC相关的TCR的作用 CD 28在T细胞活化中的作用 这些新的研究将提供T-APC的第一个四维视图 相互作用，并结合遗传和功能研究， 很有可能使人们更好地了解综合 适当调节免疫反应的事件。 这些新知识可能是 在未来设计更好的免疫监视方案中是有用的， 免疫抑制药物和新疫苗。

Cellular interactions between antigen (Ag)-specific T cells and antigen-presenting cells (APCs) can trigger either productive immune responses or aborted immune responses. These diverse biologic outcomes are determined by the complex integration of signals that are delivered upon the ligation of multiple receptors on the membrane of T cells with their counter receptors on the membrane of APCs. Uncovering the complex integrated cellular and molecular mechanisms, that determine the fate of the interacting cells, is the long term objective of these studies. Using novel 3-D digital imaging of T-APC conjugates it was recently shown that signaling and adhesion proteins are recruited to the cell contacts and form spatially segregated Supra-Molecular Activation Clusters (SMACs). This application is highly focused on the structure and function of the c-SMAC, which is the site of TCR engagement and activation. The central premise of this proposal is that TCR associated activation events are spatially and temporally orchestrated in the newly discovered c-SMAC. To test this hypothesis we will combine the use of T cell transgenic mice and multi-dimensional imaging and will define the 4-dimensional molecular translocations and association of four key activation receptors in the c-SMAC: TCR, CD45, CD4 and CD28 during T-APC interactions. These studies will be followed by derivative experiments to determine the mechanisms of association of each of these receptors with the c-SMAC and their physiological significance. The specific aims are: Aim 1. To determine the precise temporal and 3-dimensional molecular composition of c-SMACs in cell conjugates formed between T cells from TCR trangenic mice and B-APCs. Aim 2. To study the mechanisms that cause the transient colocalization of CD45 with Ag-bound TCR and Lck in early c-SMACs and to assess the functional significance of these translocations. Aim 3. To study the mechanisms that cause the transient early association of CD4 with the engaged TCR and Class II in c-SMACs, using TCR and CD4 tailless transgenic mice. Aim 4. To study the mechanisms responsible for the association of CD28 with the engaged TCR in the cSMAC and the role of c-SMAC-associated CD28 in T cell activation. These novel studies would provide the first 4-dimensional view of T-APC interactions and, in combination with genetic and functional studies, are very likely to generate significant better understanding of the integrated events that properly regulate immune responses. This new knowledge may be useful in future designs of better immune surveillance protocols, immunosupression drugs and new vaccines.