IL-2 Family Cytokines and their Receptors--Molecular Reg

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产生的量、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，总结了我们已报道的受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。此外，我们之前已经展示了这些Stat蛋白的致癌潜力。在去年证明了一些受调控的基因位于“簇”中后，该小组今年扩展了其对IL-2调控基因IL-2ra的研究，并报告了在该基因中发现了依赖Smad的TGFbeta反应元件。 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。我们先前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结合位点对T细胞中IL-7Ra的表达也是必不可少的，但在T细胞中，关键因素是GA结合蛋白(GABP)；此外，我们还通过基因捕获方法培育了GABPalpha水平降低的小鼠。GABPalpha表达降低的胚胎胸腺细胞数量明显减少，IL-7ra表达降低。在过去的一年里，我们大大扩展了我们对GABP及其在淋巴发育中的作用的研究。 最后，与IL-21系统的研究相关，该小组在确定IL-21R基因调控的基础方面取得了重大进展，报告了该基因在TCR刺激下呈现双相激活模式，并确定Sp1是一个关键的转录因子，其诱导和去磷酸化参与了这一过程。 这些发现加强了我们对调节免疫反应的基因表达的控制机制的理解，并在未来具有潜在的治疗意义。

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 genes 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. Moreover, we have previously shown the oncogenic potential of these Stat proteins. Having last year shown that some of the regulated genes are located in "clusters", the group this year extended its work of an IL-2 regulated gene, IL-2Ra, and reported the identification of a Smad-dependent TGFbeta response element in this gene. 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 was some information available 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 previously 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 additionally had previously generated mice with diminished levels of GABPalpha by a gene-trap methodology. Embryos with diminished expression of GABPalpha exhibited markedly decreased numbers of thymocytes and lower IL-7Ra expression on those cells. In the past year, we have substantially extended our studies of GABP and its role in lymphoid development. Finally, related to its study of the IL-21 system, the group made major progress in characterizing the basis for regulation of the IL-21R gene, reporting that the gene exhibits a biphasic activation pattern in response to TCR stimulation and characterizing Sp1 as a critical transcription factor whose induction and desphosphorylation was involved in this process. These findings enhance our understanding of mechanisms controlling expression of genes that regulate the immune response, with potential therapeutic implications in the future.