CD2 AND T-CELL ADHESION AND ACTIVATION

基础粘附、T细胞受体（TcR）调节 T细胞辅助受体功能和抗原中的亲合力和信号传导 反应能力很难评估。T细胞表面 糖蛋白CD 2通过结合其配体CD 58（LFA-3）和CD 59， 在T细胞活化中的双重作用，用于启动信号转导 事件并促进细胞粘附。此外，CD 2的亲合力 CD 58的表达受TcR信号的调节。为了进一步了解 参与这些关键调控过程的分子机制，野生型 人CD 2和一系列突变的CD 2分子已经在一种 鼠抗原特异性T细胞杂交瘤。结构-功能研究， 这些稳定转染的细胞系已经导致鉴定出 CD 2胞质结构域的三个不同区域， 对于信号传导（IL-2产生和cAMP的产生）， CD 2对CD 58的亲合力和细胞骨架（微管蛋白）相关性。的 细胞内的机制，重要的每一个这些功能，现在将是 研究，和一些方法来确定细胞质效应 在信号事件和亲合力期间与CD 2相互作用的分子 将采用规则。CD 2的相应部分 与其他蛋白质相互作用所需的胞质结构域将被 映射。胶粘剂与粘合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细胞活化。的潜在相关性。 将作为模型分析CD 2/微管蛋白与T细胞活化的关联 细胞骨架与膜受体相互作用的作用， 发信号。最后，研究了CD 2与CD 4相互作用的生理作用。 将研究CD 59，并与CD 2 关于CD 58 CD 2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。CD 2是免疫调节治疗的有吸引力的靶标， 它参与粘附和T细胞信号传导。结构- 功能分析可以允许鉴定特定的基序或结构域 对于基底粘附、亲合力上调、细胞骨架 相互作用和信号。这些基序将代表序列特异性 免疫调节和干预的靶点，例如， 最终用于筛选小分子的肽文库 信号传导和亲合力调节的抑制剂。的定义 CD 2/CD 58和CD 2/CD 59受体-配体的最低要求 相互作用和信号传导将有助于我们理解 调节和调节免疫反应。这种理解可能 最终导致新的免疫方法，以提高T 细胞对弱病毒或肿瘤特异性抗原的应答，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.