Molecular Mechanisms of Th1/Th2 Development

描述（由申请人提供）： 这是该计划项目赠款的第一次续期申请，目前为4年赠款的3.5年。研究的重点一直是调节Th 1和Th 2细胞因子模式平衡的分子和细胞途径。它特别致力于将特定的信号通路与重要的细胞问题相结合。这些研究利用了几种感染性和自身免疫性疾病以及免疫记忆的体内模型。它还检查了Th 1/Th 2调节的一个方面，这是不太经常考虑的，影响Th 1/Th 2平衡一旦建立的细胞相互作用;在这种情况下，通过γ/δ T细胞。该计划项目还结合了两个机构的专业知识，佛蒙特大学（UVM）和特鲁多研究所，从UVM在萨拉纳克湖，纽约两个小时。UVM研究人员（Ralph Budd，Mercedes Rincon，Sally Huber，Cory Teuscher博士）的专业知识是细胞信号传导，免疫遗传学和病毒免疫学，而Trudeau研究人员（Susan Swain，Laura Haynes和Markus Mohrs博士）在免疫记忆和细胞因子基因调控研究方面具有专业知识，这两者对我们的研究至关重要。 本项目研究的主要信号通路集中在两个重要的细胞因子基因调控转录因子NFAT和NF-kB上。IL-6通过NFATc 2触发初始CD 4 + -T细胞中的IL-4产生（项目1），而γ/δ T细胞通过NFAT表达高水平的FasL，其以Fas依赖性方式选择性地杀死Th 2细胞（项目3）。同样，c-FLIP（项目2中研究的死亡受体抑制剂）和组胺1受体（H1 R，项目4中研究的EAE易感基因位点）会聚在NF-κ B通路上，c-FLIP通过RIP向NF-κ B发出信号以共刺激T细胞，H1 R连接G蛋白和PKC θ向NF-κ B发出信号。所有四个项目都研究了这些信号通路和细胞类型如何影响Th 1/Th 2环境。此外，项目1和2还研究了c-FLIP/NF-kappaB和IL-6/NFAT通路如何影响效应Th 1/Th 2向记忆CD 4 + T细胞的转变。 在目前的资助期间取得了实质性进展（超过30篇出版物），其中8篇是项目研究者的多作者，更新申请包括两名新研究者，Cory Teuscher博士，一位领先的免疫遗传学家，和Markus Mohrs博士，在细胞因子基因调控方面具有专业知识。

DESCRIPTION (provided by applicant): This is the first renewal application for this Program Project Grant, currently at 3.5 years of a 4 year grant. The focus has been and remains a study of the molecular and cellular pathways that regulate the balance of Th1 and Th2 cytokine patterns. It makes a particular effort to integrate specific signal pathways with important cellular questions. These studies make use of several in vivo models of infectious and autoimmune diseases as well as immune memory. It also examines an aspect of Th1/Th2 regulation that is less frequently considered, the cellular interactions that influence the Th1/Th2 balance once it is established; in this case by gamma/delta T cells. This Program Project also combines the expertise of two institutions, The University of Vermont (UVM) and the Trudeau Institute, two hours from UVM in Saranac Lake, NY. The UVM investigators (Drs. Ralph Budd, Mercedes Rincon, Sally Huber, Cory Teuscher) have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators (Drs. Susan Swain, Laura Haynes, and Markus Mohrs) have expertise in the study of immune memory and cytokine gene regulation, both of which are critical to our studies. The principal signal pathways studied in this Program Project converge on two important transcription factors for cytokine gene regulation, NFAT and NF-kB. IL-6 triggers IL-4 production in naive CD4+ -T cells via NFATc2 (Project 1), whereas gamma/delta T cells express high levels of FasL via NFAT which selectively kill Th2 cells in a Fas-dependent manner (Project 3). Similarly, c-FLIP (the death receptor inhibitor studied in Project 2) and the Histamine 1 Receptor (H1R, a susceptibility gene locus for EAE studied in Project 4) converge on the NF-kB pathway, c-FLIP signals NF-kappaB via RIP to costimulate T cells, and H1R connects to G-proteins and PKC theta to signal NF-kappaB. All four projects examine how these signal pathways and cell types influence the Th1/Th2 environment. In addition, Projects 1 and 2 also examine how the c-FLIP/NF-kappaB and IL-6/NFAT pathways influence the transition from effector Th1/Th2 to memory CD4+ T cell. Progress during the current funding period has been substantial (over 30 publications), 8 of which are multi-authored among the Program investigators, the renewal application includes two new investigators, Dr. Cory Teuscher, a leading immunogeneticist, and Dr. Markus Mohrs, with expertise in cytokine gene regulation.