CD2 AND T-CELL ADHESION AND ACTIVATION

基础黏附、T细胞受体(TCR)调节的相关作用 亲和力、T细胞辅受体功能和抗原的信号转导 反应能力一直很难评估。T细胞表面 糖蛋白CD2通过结合其配体CD58(LFA-3)和CD59发挥作用 T细胞激活中的双重作用，用于启动信号转导 活动和促进细胞粘附力。此外，CD2的亲和力 CD58受TCR信号调节。为了进一步深入了解 参与这些关键调控过程的分子机制，野生型 人CD2和一系列突变的CD2分子已在 小鼠抗原特异性T细胞杂交瘤。结构-功能研究使用 这些稳定转染的细胞系导致了对 CD2胞质区域的三个不同区域是必需的 对于信号(IL-2的产生和cAMP的产生)，TCR调节 CD2对CD58的亲和力和细胞骨架(微管蛋白)的相关性。这个 对这些功能都很重要的细胞内机制现在将是 研究，以及识别细胞质效应器的一些方法 在信号传递和亲和力过程中与CD2相互作用的分子 将采用监管措施。CD2的各个部分 与其他蛋白质相互作用所需的细胞质结构域将是 已映射。胶粘剂和胶粘剂之间复杂相互作用的研究 分子水平上的信号事件对于理解 调节T细胞的激活。潜在的关联性 CD2/微管蛋白与T细胞活化的关系将作为一个模型进行分析 细胞骨架与膜受体相互作用在细胞周期调控中的作用 发信号。最后，CD2与CD2相互作用的生理作用 我们将研究CD59，并将其与CD2的相互作用进行比较 使用CD58。 CD2相互作用的研究作为定义的模型系统 细胞质的结构要求和生物效应 发信号。CD2是免疫调节治疗的一个有吸引力的靶点，因为 它同时参与黏附和T细胞信号转导。这个结构-- 功能分析可以识别特定的基序或结构域 对于基础黏附、亲和力上调、细胞骨架很重要 相互作用和信号传递。这些主题将代表特定于序列的 免疫调节和干预的目标，并且可以，例如， 最终用于筛选小分子多肽文库 信号和亲和力调节的抑制物。定义的定义 CD2/CD58和CD2/CD59受体配体的最低要求 相互作用和信号传递将有助于我们理解 调节和调节免疫反应。这一理解可能 最终导致新的免疫治疗方法来增强T细胞 细胞对弱病毒或肿瘤特异性抗原的反应，或调节 自身免疫性疾病中的T细胞反应。

The relative roles of basal adhesion, T cell receptor (TcR)-regulation of avidity, and signaling in T cell coreceptor function and antigen responsiveness have been difficult to assess. The T cell surface glycoprotein CD2, by binding its ligands CD58 (LFA-3) and CD59, plays a dual role in T cell activation, serving to initiate signal transduction events and to promote cellular adhesion. Furthermore, the avidity of CD2 for CD58 is regulated by TcR signaling. To gain further insight into the molecular mechanisms involved in these key regulatory processes, wild-type human CD2 and a series of mutated CD2 molecules have been expressed in a murine antigen-specific T cell hybridoma. Structure-function studies using these stably transfected cell lines have led to the identification of three distinct regions of the cytoplasmic domain of CD2 that are required for signaling (IL-2 production and generation of cAMP), TcR-regulation of avidity of CD2 for CD58, and cytoskeletal (tubulin) associations. The intracellular mechanisms important for each of these functions will now be investigated, and a number of approaches to identify cytoplasmic effector molecules that interact with CD2 during signaling events and avidity regulation will be employed. The respective portions of the CD2 cytoplasmic domain required for interaction with other proteins will be mapped. An investigation of the complex interplay between adhesive and signaling events at the molecular level is essential to understanding the regulation of T cell activation. The potential relevance of the CD2/tubulin association to T cell activation will be analyzed as a model of the role of the cytoskeletal interactions with membrane receptors in signaling. Lastly, the physiological role of the interaction of CD2 with CD59 will be investigated and compared to that of the interaction of CD2 with CD58. The study of CD2 interactions serves as a model system for the definition of the structural requirements and the biological effectors of cytoplasmic signaling. CD2 is an attractive target for immunomodulatory therapies as it is involved both in adhesion and T cell signaling. The structure- function analysis may allow identification of specific motifs or domains important for basal adhesion, upregulation of avidity, cytoskeletal interactions, and signaling. These motifs will represent sequence-specific targets for immune modulation and interventions, and may, for example, ultimately be used for screening peptide libraries for small molecule inhibitors of signaling and avidity regulation. The definition of the minimum requirements for the CD2/CD58 and CD2/CD59 receptor-ligand interactions and for signaling will contribute to our understanding of the regulation and modulation of the immune response. This understanding may ultimately lead to novel immunotherapeutic approaches to enhance the T cell response to weak viral or tumor specific antigens, or to modulate the T cell response in autoimmune disease.