FUNCTION OF THE HUMAN CD28 MOLECULE

对微生物的免疫反应和同种异体移植的排斥反应发生在 抗原特异性淋巴细胞活化的结果。激活T细胞 淋巴细胞受分子间结合事件的调节，这些结合事件发生在 抗原特异性T细胞和抗原提呈细胞的界面。 尽管T细胞抗原受体(TCR)在调节 抗原特异性T细胞激活，其他细胞表面分子起作用 在这个激活过程中。一个特别感兴趣的分子，这是 提案的重点是CD28，一种44kD单体的同源二聚体。抗CD28抗体 单抗9.3在高浓度时可激活T细胞。 然而，它更有效地与结合到 TCR或与模拟TCR介导的信号的药物一起使用 转导。虽然TCR介导的T细胞活化是环孢素A 通过CD28的敏感激活则不是。这些结果表明CD28 调节与TCR不同的信号转导事件。因此， CD28可能调节一条重要的共刺激通路，该通路有助于 T细胞活化。 这项应用建议检测CD28在T细胞中的功能 激活。具体目标将集中在CD28在 白细胞介素2等淋巴因子的转录调控 CD28在生理性抗原反应中的作用 CD28的功能和识别CD28的重要特征 CD28介导的信号转导事件。 初步实验结果表明，CD28能增强细胞外基质的活性。 IL-2增强剂。我们已经确定了一种CD28诱导的核因子 白介素2增强剂。我们建议确定增强子的位置，即 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 用于其他淋巴因子。此外，我们建议使用该转录 以调控机制为探针考察CD28在人类免疫缺陷中的重要性 抗原特异性反应。 使用一种细胞重建系统，我们在我们的初步研究中描述了这种系统 结果，我们建议确定CD28分子的区域 在信号转导中很重要。这些研究将扩展到 描述CD28调控的信号转导途径。

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.