GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

已发现T细胞耐受性发生在未成熟的T细胞中 胸腺和胸腺外成熟的T细胞。我们对成熟度的研究 T耐受性表明，它们可能会被删除或输入 功能上无反应的状态称为无能。在无能为力中，一个T帮手 如果细胞受到刺激，可以诱导其“关闭”IL-2的产生 在没有共刺激的情况下通过它的T细胞受体。先前 我们发现，控制IL-2基因表达的调节蛋白可能 在无能T细胞中对抗原的反应很差。一 T细胞是否会被正常激活的重要决定因素 遇到抗原/MHC复合体的问题是它是否与 共同刺激的刺激。共刺激是由 表面分子如CD28(在T细胞上)与B7或 BB-1(在抗原提呈细胞上)。协同刺激的存在 似乎是正常T细胞增殖反应所必需的 抗原。为了了解协同刺激在IL-2产生中的作用， 我们研究了共刺激对脑内各种元素的影响。 IL-2启动子。到目前为止，这些研究表明，转录 启动子中的某些顺式元件的功能可以通过共同的 刺激性影响。进一步的研究正在进行中，以进一步 定义所涉及的分子机制。最后，一个重要的方面 对入侵的微生物的免疫反应的成功 似乎是辅助性T细胞对 产生IL-2(TH1细胞)或IL-4(TH2细胞)的细胞。我们有 研究了IL-4基因启动子中的调控元件和 检测到一个转录反式激活子及其结合位点(CS-1) 在TH2细胞中表达受限制且对其至关重要的基因。

T cell tolerance has been found to occur in immature T cells in the thymus and also extrathymically in mature T cells. Our studies of mature T tolerance has revealed that they may undergo deletion or enter a functionally unresponsive state termed anergy. In anergy, a T-helper cell can be induced to "turn off" IL-2 production if it is stimulated through its T-cell receptor in the absence of costimulation. Previously we showed that regulatory proteins that govern IL-2 gene expression may be poorly activatable in response to antigen in anergic T cells. One important determinant of whether T cells will be normally activated by encountering an antigen/MHC complex is whether it is presented along with a co-stimulatory stimulus. Co-stimulation is the signal provided by the interaction of surface molecules such as CD28 (on the T cell) and B7 or BB-1 (on the antigen-presenting cell). The presence of co-stimulation seems to be required for the normal T cell proliferative response to antigen. To understand the role of co-stimulation in IL-2 production, we have studied the effects of co-stimulation on various elements in the IL-2 promoter. Thus far these studies indicate that the transcriptional function of certain cis elements in the promoter can be augmented by co- stimulatory influences. Further studies are in progress to further define the molecular mechanisms involved. Finally, an important aspect of the success of an immune response to an invading micro-organism appears to be the specialization of the helper T cell response towards cells that either produce IL-2 (TH1 cells) or IL-4 (TH2 cells). We have studied the regulatory elements in the promoter of the IL-4 gene and detected a transcriptional trans-activator and its binding site (CS-1) that are restricted to and crucial for expression in TH2 cells.