LYMPHOCYTE SIGNALLING PATHWAYS INVOLVING NUCLEAR FACTOR KAPPA B REGULATORS

几种淋巴因子及其他分子的基因调控 参与免疫反应依赖于一个10个碱基对的DNA序列 卡帕B。该序列结合了一系列与核蛋白相关的核蛋白 哺乳动物的rel癌基因和果蝇的背部蛋白。重要的是 KappaB序列在人类免疫缺陷病毒(HIV)中被发现。 我们建立了一套研究未转化T细胞中的核因子-kappaB的系统 抗原和抗原提呈细胞刺激后的克隆 (APCS)。最近，我们重点比较了各种不同的监管 CD4+T淋巴细胞TH1和TH2亚群中的核因子-kappaB亚基。它 相信可能存在从TH1到TH2子集的切换 艾滋病的晚期病程。因此，我们一直在研究 人类免疫缺陷病毒的转录激活功能 由核因子-kappaB调控的长末端重复序列(HIV-LTR)。我们的 初步研究结果表明，HIV LTR在TH2细胞中更活跃 这表明病毒的产生可能在后期加速。 在从TH1到TH2的转换过程中感染艾滋病。进一步的工作将针对以下方面 确认和扩展这些发现，并确定不同的 核因子-kappaB家族的亚基调节HIV内的结合部位 Ltr. T细胞中抗原信号最有趣的特征之一是 同样的T细胞受体(TCR)复合体可以导致激活，这 包括核因子-kappaB的诱导，或程序性细胞死亡(细胞凋亡)。 区分这两种结果的信号通路是 未知。我们已经开始了系统地诱变 TCR的CD3和Zeta部分的细胞质信号部分 确定激活的信令要求和 死亡。我们发现Zeta细胞质部分是必需的 足以诱导细胞凋亡，而Zeta和CD3 epsilon 胞浆内部分可发出包括核因子-kappaB在内的激活信号 诱导和IL-2表达。进一步广泛的诱变表明 这种特定的氨基酸序列称为“免疫受体酪氨酸基” 存在于细胞质区域的激活基序“(ITAM) 不同的信号链在诱导中具有不同的作用 激活和死亡。

Regulation of genes for several lymphokines as well as other molecules involved in the immune response depend on a 10 bp DNA sequence termed kappaB. This sequence binds a family of nuclear proteins related to the mammalian Rel oncogene and the drosophila protein, dorsal. Importantly, the kappaB sequence is found in the human immunodeficiency virus (HIV). We have established a system to study NF-kappaB in nontransformed T cell clones following stimulation by antigen and antigen-presenting cells (APCs). Recently we have focused on comparing the regulation of various NF-kappaB subunits in the TH1 and TH2 subsets of CD4+ T lymphocytes. It is believed that there may be a switch from the TH1 to the TH2 subset in the late course of AIDS. We have therefore been studying the transcriptional activating function of the human immunodeficiency virus long terminal repeat (HIV LTR) which is controlled by NF-kappaB. Our preliminary findings suggest that the HIV LTR is more active in TH2 cells suggesting that viral production might be accelerated in the late phases of AIDS during the TH1 to TH2 switch. Further work will be directed at confirming and extending these findings and determining how various subunits of the NF-kappaB family regulate the binding site within the HIV LTR. One of the most interesting features of antigen signalling in T cells is that the same T cell receptor (TCR) complex can lead to activation, which includes NF-kappaB induction, or to programmed cell death (apoptosis). The signal pathways that discriminate between these two outcomes are unknown. We have initiated studies to systematically mutagenize the cytoplasmic signalling portions of the CD3 and zeta portions of the TCR complex to determine the signalling requirements for activation and death. We have found that the zeta cytoplasmic portion is necessary and sufficient for apoptosis, whereas zeta and the CD3 epsilon intracytoplasmic portion can signal for activation including NF-kappaB induction and IL-2 expression. Further extensive mutagenesis has shown that specific amino acid sequences called "immunoreceptor tyrosine-based activation motifs" (ITAMS) that are present in the cytoplasmic regions of the various signalling chains have differential effects in inducing activation and death.