Il2 Receptors--molecular regulation

Il2受体--分子调控

• 批准号: 6967133
• 负责人: Warren J Leonard
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6967133
• 关键词: T lymphocyte; biological signal transduction; cellular immunity; cytokine receptors; cytotoxic T lymphocyte; gene targeting; genetic regulation; genetically modified animals; human tissue; immunogenetics; interleukin 2; interleukin 7; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer immunology; protein structure function; receptor expression; thymus neoplasms; tissue /cell culture; transcription factor

The human interleukin-2 receptor and related cytokine/cytokine receptor systems are being studied to understand critical components of the T cell immune response in normal and neoplastic cells. Following T-cell activation, IL-2 and IL-2 receptors are induced; the magnitude and duration of the T-cell immune response is controlled by the amount of IL-2 produced, the levels of receptors expressed, and the time course of these events. Three chains of the IL-2 receptor exist, IL-2Ra, IL-2Rb, and gc, with IL-2Ra and IL-2Rb being significantly regulated at the level of transcription. gc is a shared chain also used by the receptors for IL-4, IL-7, IL-9, IL-15, and IL-21, and is the protein that is mutated in XSCID. The group has focused primarily on the types of signals induced by IL-2, particularly the activation of STAT proteins (signal transducers and activators of transcription), and the mechanism by which they regulate the IL-2Ra gene and other IL-2 induced genes. In the accompanying annual report, it is summarized that we have reported the characterization of a large number of genes that are regulated by gc dependent cytokines. Many of these appear to be dependent on two closely-related Stat5 proteins, denoted Stat5a and Stat5b, and we have previously demonstrated that these two proteins critically control IL-2 receptor alpha chain gene regulation by binding to two widely separated IL-2 response elements. Stat5a and Stat5b are two closely related proteins with >90% amino acid identity that are activated by IL-2. The genes encoding Stat5a and Stat5b are adjacent and the genes are located in a head-to-head orientation. An important issue is whether these closely related proteins are redundant or distinctive in their actions. To attempt to clarify this issue, Stat5a and Stat5b transgenic mice were generated to reconstitute the knockout mice. In addition, aspects of similarities vs. differences in regulation of these genes are being studied. The phenotype of Stat5a and Stat5b transgenic mice was striking. Our studies revealed that these proteins play a major role in the regulation of CD8+ T cell homeostasis and these findings were reported. Moreover, as the mice aged, they developed thymic lymphoblastic lymphoma, even though they did not exhibit a constitutively activated Jak-STAT pathway. The basis for this malignancy is being investigated further. Previously, we and others demonstrated that a constitutively activated Jak-STAT pathway correlates with and perhaps is causal in the development of certain malignancies. Thus, these thymic lymphomas may be distinctive. DNA array profiling revealed some genes that are induced in the tumors but not in the non-tumor bearing transgenic mice. These findings are important in teaching more about the effects of Stat5 expression and link our earlier signaling studies to oncogenesis. In the associated report, it is noted that we previously demonstrated that IL-7 receptor alpha chain expression is potently negatively regulated by IL-2. Although there is some information regarding the basis for regulation of the IL-7 receptor in B cells, essentially nothing was known in T cells. In B cells, an Ets family transcription factor, PU.1, is critical for control of the gene. We now have defined and reported the transcription initiation site for the gene, and discovered that the same Ets binding site that binds PU.1 in B cells is also essential for IL-7Ra expression in T cells, but that in T cells, the critical factor is GA binding protein (GABP). We generated mice with diminished levels of GABPalpha by a gene-trap methodology. Embryos with diminished expression of GABPalpha exhibited marked diminished numbers of thymocytes and diminished IL-7Ra on those cells. In contrast fetal liver B cells had normal levels of IL-7R expression. These data indicate that differential regulation of IL-7Ra in distinct lymphoid lineages is achieved at lleast in part by differential recruitment of factors to the same GGAA motif.

人们正在研究人类白介素2受体和相关的细胞因子/细胞因子受体系统，以了解正常细胞和肿瘤细胞中T细胞免疫反应的关键成分。T细胞激活后，IL-2和IL-2受体被诱导；T细胞免疫反应的大小和持续时间由IL-2的生成量、受体的表达水平和这些事件的时间进程控制。IL-2受体存在三条链，即IL-2Ra、IL-2Rb和GC，其中IL-2Ra和IL-2Rb在转录水平上受到显著调控。GC是IL-4、IL-7、IL-9、IL-15和IL-21受体的共享链，是XSCID中突变的蛋白质。该小组主要关注IL-2诱导的信号类型，特别是STAT蛋白(信号转导和转录激活因子)的激活，以及它们调节IL-2ra基因和其他IL-2诱导基因的机制。在随附的年度报告中，我们总结了大量受GC依赖细胞因子调控的基因的特征。其中许多似乎依赖于两个密切相关的Stat5蛋白，分别表示为Stat5a和Stat5b，我们先前已经证明，这两个蛋白通过与两个广泛分离的IL-2反应元件结合来关键地控制IL-2受体α链基因的调控。 Stat5a和Stat5b是两个密切相关的蛋白质，它们被IL-2激活，具有90%的氨基酸同源性。编码Stat5a和Stat5b的基因是相邻的，并且这两个基因位于头对头的方向。一个重要的问题是，这些密切相关的蛋白质在它们的作用中是多余的还是独特的。为了澄清这一问题，我们培育了Stat5a和Stat5b转基因小鼠来重建基因敲除小鼠。此外，这些基因调控方面的相似性和差异性正在研究中。Stat5a和Stat5b转基因小鼠的表型显著。我们的研究表明，这些蛋白在调节CD8+T细胞的动态平衡方面起着重要作用，这些发现已被报道。此外，随着年龄的增长，它们会患上胸腺淋巴母细胞性淋巴瘤，尽管它们没有表现出结构性激活的JAK-STAT通路。这种恶性疾病的基础正在进一步调查中。以前，我们和其他人证明了结构性激活的JAK-STAT通路与某些恶性肿瘤的发展相关，而且可能是因果关系。因此，这些胸腺淋巴瘤可能是独特的。DNA阵列图谱显示，一些基因在肿瘤中诱导，但在非携带肿瘤的转基因小鼠中不诱导。这些发现对于教授更多关于Stat5表达的影响并将我们早期的信号研究与肿瘤发生联系起来具有重要意义。 在相关的报告中，我们注意到我们先前证明了IL-7受体阿尔法链的表达受到IL-2的有效负调控。虽然有一些关于调节B细胞中IL-7受体的基础的信息，但基本上对T细胞一无所知。在B细胞中，ETS家族转录因子PU.1对该基因的控制至关重要。我们现在已经定义并报道了该基因的转录起始点，并发现在B细胞中与PU.1结合的相同ETS结合位点也是T细胞表达IL-7ra所必需的，但在T细胞中，关键因子是GA结合蛋白(GABP)。我们通过基因捕捉方法产生了GABPalpha水平降低的小鼠。GABPalpha表达降低的胚胎表现为胸腺细胞数量显著减少，这些细胞上的IL-7ra减少。而胎肝B细胞IL-7R表达水平正常。这些数据表明，IL-7ra在不同淋巴谱系中的不同调节至少部分是通过对同一GGAA基序不同的因子招募实现的。