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反应是作为一种免疫反应而发生的。 抗原特异性淋巴细胞活化的结果。 活化T 淋巴细胞是由分子间的结合事件，发生在 抗原特异性T细胞和抗原呈递细胞界面。 尽管T细胞抗原受体（TCR）在调节免疫应答中起主要作用， 抗原特异性T细胞活化，其他细胞表面分子有助于 这个激活过程。 一种特别的分子 该提案关注的是CD 28，44 kD单体的同源二聚体。 抗CD 28 单克隆抗体9.3在高浓度下可以激活T细胞。 然而，它在与结合到受体的激动剂协同作用方面更有效。 TCR或与模拟TCR介导的信号的药物 转导 虽然TCR介导的T细胞活化是环孢菌素 通过CD 28的敏感性激活不是。 这些结果表明，CD 28 调节不同于TCR的信号转导事件。 因此，在本发明中， CD 28可能调节一个重要的共刺激通路， T细胞活化。 本申请提出检测T细胞中CD 28的功能， activation. 具体目标将侧重于CD 28在 白细胞介素2（IL-2）和其他淋巴因子的转录调节 基因，对CD 28在生理抗原应答中的作用， CD 28的特征在其功能和识别 CD 28介导的信号转导事件。 初步结果表明，CD 28可以增加 IL-2增强剂。 我们已经确定了一种CD 28诱导的核因子， IL-2增强剂 我们建议确定增强子的位点， 受CD 28调节，并表征与其结合的因子。我们将 确定这种转录调节机制是否重要 其他淋巴因子。 此外，我们建议使用这种转录 调节机制作为探针，以检查CD 28在 抗原特异性反应。 使用细胞重建系统，我们在我们的初步表征， 结果，我们建议确定CD 28分子的区域， 在信号转导中起重要作用。 这些研究将扩大到 表征由CD 28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.