GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

已经发现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T细胞。 我们的研究成熟 T细胞耐受性揭示了这些细胞可能经历缺失或进入 一种功能性无反应的状态称为无反应性。 在无反应时， 细胞可以被诱导“关闭”IL-2的产生，以响应典型的 刺激配体，如果它首先通过其T细胞受体发出信号 在没有共刺激的情况下。 之前我们已经证明， 控制IL-2基因表达的蛋白质可能在 无反应性T细胞对抗原的反应。 一个重要的决定因素 T细胞是否会因遇到抗原/MHC而被正常激活 复杂性在于它是否与共刺激刺激一起沿着呈现。 共刺激是由表面相互作用提供的信号 分子如CD 28（在T细胞上）和CD 80或CD 86（在T细胞上）。 抗原呈递细胞）。 共刺激的存在似乎 正常T细胞对抗原的增殖反应所需。 到 为了了解共刺激在IL-2产生中的作用，我们研究了 共刺激对IL-2启动子中各种元件的影响。 到目前为止，这些研究表明， 启动子中的某些顺式元件可以通过共刺激增强 影响。 进一步的研究正在进行中，以确定分子 涉及的机制更详细。 最后， 对入侵微生物的免疫反应的成功似乎 是辅助T细胞对细胞反应的特化， 产生IL-2（TH 1细胞）或IL-4（TH 2细胞）。 我们研究了 IL-4基因启动子中的调控元件，并检测到 转录反式激活因子及其结合位点（CS-1）， 仅限于TH 2细胞，对TH 2细胞的表达至关重要。 最近工作 来自其他实验室的研究表明， CS-1位点包括NF-AT和c-maf原癌基因的结合位点。 c-maf原癌基因似乎在TH 2中特异性表达， 细胞 我们将分析c-maf的调节，以了解它是如何 调控淋巴因子基因表达的分化和功能 TH 2 CD 4 + T淋巴细胞。 我们还计划解剖IL-2启动子， 确定区域，以积极或消极的贡献， 它在TH 1细胞中的专门表达。

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 have revealed that these cells 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 in response to typical stimulatory ligands if it is first signaled 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 CD80 or CD86 (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 define the molecular mechanisms involved in more detail. 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. Recently work from other labs has indicated that the promoter region containing the CS-1 site includes binding sites for NF-AT and the c-maf proto-oncogene. The c-maf proto-oncogene appears to be expressed specifically in TH2 cells. We will analyze the regulation of c-maf to understand how it governs lymphokine gene expression in the differentiation and function of TH2 CD4+ T lymphocytes. We also plan to dissect the IL-2 promoter to determine the regions that serve to positively or negatively contribute to its specialized expression in TH1 cells.