EARLY GENE EXPRESSION DURING T CELL ACTIVATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。适当的T细胞分化是正常免疫反应的关键组成部分，并确保对包括微生物病原体在内的各种损害具有足够的免疫力。在T细胞分化过程中，细胞因子位点发生染色质结构的显著变化，促进细胞因子基因的协调表达。我们最近发现，组蛋白乙酰化的改变，加上细胞因子基因转录，发生在T细胞刺激的几个小时内。有趣的是，转录模式和染色质重塑与Th1/Th2极化无关。细胞因子位点启动子组蛋白修饰的早期变化是可塑的，可以根据T细胞随后遇到的细胞因子环境维持或逆转。本研究的目标是研究细胞因子早期转录以及细胞因子位点周围局部染色质环境的变化，以确定这些早期变化是否为随后的效应分化奠定了基础，从而可能是细胞命运的重要决定因素。本提案的科学目的是研究非承诺T细胞中T辅助细胞因子的早期转录调控。我们假设这种早期转录是决定效应细胞最终分化状态的关键步骤。我们将评估细胞因子位点内染色质重塑在这种早期转录中的作用，并将这些事件与分化效应细胞中的事件进行比较。不适当的T细胞分化与许多病理状态有关，是免疫反应的关键决定因素。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Appropriate T cell differentiation is a critical component of a normal immune response and insures sufficient immunity to a variety of insults, including microbial pathogens. During T cell differentiation, the cytokine loci undergo significant changes in chromatin structure that facilitate coordinated expression of the cytokine genes. We recently found that altered histone acetylation, coupled with cytokine gene transcription, occur within hours of T cell stimulation. Interestingly, the patterns of transcription and chromatin remodeling were independent of Th1/Th2 polarization. The early changes in histone modifications at the promoters of the cytokine loci were plasic and could be maintained or reversed depending on the cytokine environment that the T cells encountered subsequently. The goal of this proposal is to examine early cytokine transcription as well as changes in the local chromatin environment around the cytokine loci to determine whether these early changes set the stage for subsequent effector differentiation and thus may be an important determinant of cell fate. The scientific aims of this proposal are to study the regulation of early transcription of T helper cytokines in uncommitted T cells. We hypothesize that this early transcription is a critical step in determining the ultimate differentiated state of the effector cells. We will assess the role of chromatin remodeling within the cytokine loci on this early transcription and compare these events to those in differentiated effector cells. Inappropriate T cell differentiation has been implicated in a number of pathological states and is a critical determinant of immune responsiveness.