FUNCTION OF THE HUMAN CD28 MOLECULE

对微生物的免疫反应和同种异体移植物的排斥作为 抗原特异性淋巴细胞激活的结果。 激活T 淋巴细胞受分子间结合事件的调节，这些事件发生在 抗原特异性 T 细胞和抗原呈递细胞的界面。 尽管 T 细胞抗原受体 (TCR) 在调节中起主要作用 抗原特异性 T 细胞激活，其他细胞表面分子贡献 到这个激活过程。 一种特定的感兴趣分子 该提案的重点是 CD28，一种 44kD 单体的同型二聚体。 抗CD28 单克隆抗体9.3，高浓度时可激活T细胞。 然而，它与结合到的激动剂具有更有效的协同作用。 TCR 或模拟 TCR 介导信号的药物 转导。 虽然TCR介导的T细胞激活是环孢素 通过 CD28 激活则不敏感。 这些结果表明 CD28 调节与 TCR 不同的信号转导事件。 因此， CD28可能调节重要的共刺激途径，从而有助于 T 细胞激活。 本申请旨在检查 T 细胞中 CD28 的功能 激活。 具体目标将集中于 CD28 在 白细胞介素 2 (IL-2) 和其他淋巴因子的转录调节 基因、CD28 在生理抗原反应中的作用、结构 CD28 的特征对于其功能和识别非常重要 CD28 介导的信号转导事件。 初步结果表明 CD28 可以增加 IL-2增强剂。 我们已经鉴定出 CD28 诱导的核因子 至 IL-2 增强子。 我们建议确定增强子的位点 受 CD28 调节并表征与其结合的因子。 我们会 确定这种转录调控机制是否重要 对于其他淋巴因子。 此外，我们建议使用这种转录 调节机制作为检查 CD28 在细胞中的重要性的探针 抗原特异性反应。 使用我们在初步研究中描述的细胞重建系统 结果，我们建议确定 CD28 分子的区域 在信号转导中很重要。 这些研究将延伸至 表征受 CD28 调节的信号转导途径。

Immune responses to microorganisms and rejection of allografts occur as a result of the activation of antigen specific lymphocytes. Activation of T lymphocytes is regulated by intermolecular binding events that occur at the interface of antigen-specific T cell and an antigen presenting cell. Although the T cell antigen receptor (TCR) plays a major role in regulating antigen-specific T cell activation, other cell surface molecules contribute to this activation process. One particular molecule of interest which this proposal focuses on is CD28, a homodimer of 44kD monomers. The anti-CD28 monoclonal antibody 9.3, at high concentrations can activate T cells. However, it is more potent in synergizing with agonists that bind to the TCR or with pharmacologic agents which mimic TCR-mediated signal transduction. Although TCR-mediated activation of T cells is cyclosporin A sensitive, activation via CD28 is not. These results suggest that CD28 regulates a signal transduction event distinct from that of the TCR. Thus, CD28 may regulate an important costimulatory pathway which contributes to T cell activation. This application proposes to examine the function of CD28 in T cell activation. Specific aims will focus on the role of CD28 on the transcriptional regulation of interleukin 2 (IL-2) and other lymphokine genes, on the role of CD28 in physiologic antigen responses, on structural features of CD28 that are important in its function and on identifying the signal transduction events mediated by CD28. Preliminary results demonstrate that CD28 can increase the activity of the IL-2 enhancer. We have identified a CD28-induced nuclear factor that binds to the IL-2 enhancer. We propose to identify the site of enhancer that is regulated by CD28 and characterize the factor that binds to it. We will determine whether this mechanism of transcriptional regulation is important for other lymphokines. Moreover, we propose to use this transcriptional regulatory mechanism as a probe to examine the importance of CD28 in antigen specific responses. Using a cell reconstitution system which we characterize in our preliminary results, we propose to identify the regions of the CD28 molecule that are important in signal transduction. These studies will be extended to characterize the signal transduction pathway that is regulated by CD28.