MOLECULAR MECHANISMS OF TH1/TH2 DEVELOPMENT

TH1/TH2 发育的分子机制

• 批准号: 6374189
• 负责人: Ralph C Budd
• 金额: $ 65.23万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374189
• 关键词: cell population study; developmental immunology; helper T lymphocyte

This Multi-Project Program investigates the regulation of Th1 and Th2 cells at two specific levels, control by gammadelta T cells and by transcription. The first two projects study the model the gammadelta T cells promote a Th1 environment by selectively killing Th2 cells. This model evolved from work in two laboratories. Dr. Sally Huber showed that susceptibility to murine Coxsackievirus (CVB3)-induced autoimmune myocarditis correlated with a Th1 response and resulted from gammadelta T cell-mediated death of Th2 cells. Dr. Ralph Budd showed that gammadelta T cells selectively kill differentiated Th2 cells, but spare Th1 cells during the pathogenesis of Borrelia Burgdorferi- induced Lyme arthritis. In the Coxsackievirus system, depletion of gammadelta T cells alleviated the myocarditis and left a Th2 response whereas adoptive transfer of gammadelta T cells enhanced disease and a Th1 response. Drs. Karen Newell and Huber have extended these results showing that expression of MHC class II IE in resistant C57BL/6 mice renders them susceptible to CVB3 myocarditis. This susceptibility is alleviated by the removal of gammadelta T cells which results in a Th2 response. Project 1 uses in vivo murine systems in Drs. Newell and Huber s laboratories, and in vitro murine systems with Dr. Susan Swain s group, to establish a link between expression of MHC class II IE molecules and the activation of gammadelta T cells that kill Th2 cells during the course of Coxsackieviral infection. Project 2 uses human synovial Vdelta1 T cell clones to determine if gammadelta T cells bias the Cd4+ immune response in vitro by selectively lysing Th2 cells in a Fas (CD95)-dependent manner. These two projects are complementary and will provide a basis for comparison between Coxsackievirus and Borrelia Burgdorferi- induced autoimmune diseases. Surviving antigen-specific T cells provide long lived specific memory. Little is known of the regulatory mechanisms that control the balance between naive, effector Th1 and Th2, and ultimately memory T cell responses to antigens. Dr. Mercedes Rincon s group has shown that Th2 effector cells manifest considerably more NFAT and AP-1 transcriptional activity than Th1 cells. In Project 3 Dr. Rincon will extend these findings to determine a) mechanisms that regulate NFAT transcriptional activity in naive, effector Th1 and Th2, and memory CD4+ T cells, and b) the role of specific NFAT family members in the activation, differentiation, and survival of these CD4+ T cell populations. These studies will provide information about the cellular regulation of effector Th1 and Th2 cells (Projects 1 and 2) as well as the molecular regulation of cytokine differentiation during the transition from naive to become memory T cells (Project 3).

这个多项目计划研究了Th 1和Th 2细胞在两个特定水平的调节，由γ δ T细胞和转录控制。 前两个项目研究的是γ δ T细胞通过选择性杀死Th 2细胞来促进Th 1环境的模型。 这个模型是由两个实验室的工作发展而来的。 Sally Huber博士表明，对小鼠柯萨奇病毒（CVB 3）诱导的自身免疫性心肌炎的易感性与Th 1应答相关，并由γ δ T细胞介导的Th 2细胞死亡引起。 Ralph Budd博士表明，在伯氏疏螺旋体诱导的莱姆关节炎的发病过程中，γ δ T细胞选择性地杀死分化的Th 2细胞，但不杀死Th 1细胞。 在柯萨奇病毒系统中，γ δ T细胞的耗竭减轻了心肌炎并留下了Th 2应答，而γ δ T细胞的过继转移增强了疾病和Th 1应答。 Karen纽韦尔和Huber博士扩展了这些结果，表明在抗性C57 BL/6小鼠中表达MHC II类IE使它们对CVB 3心肌炎易感。 这种易感性通过去除γ δ T细胞而减轻，这导致Th 2应答。 项目1使用纽韦尔博士和Huber博士实验室的体内鼠系统，以及Susan Swain博士小组的体外鼠系统，以建立在柯萨奇病毒感染过程中MHC II类IE分子的表达与杀死Th 2细胞的γ δ T细胞的激活之间的联系。 项目2使用人滑膜Vdelta 1 T细胞克隆来确定γ δ T细胞是否通过以Fas（CD 95）依赖性方式选择性地裂解Th 2细胞来在体外偏向Cd 4+免疫应答。这两个项目是互补的，并将为柯萨奇病毒和伯氏疏螺旋体诱导的自身免疫性疾病之间的比较提供基础。存活的抗原特异性T细胞提供长寿命的特异性记忆。 很少有人知道的调节机制，控制幼稚，效应Th 1和Th 2之间的平衡，并最终记忆T细胞对抗原的反应。 Mercedes Rincon博士的研究小组已经表明，Th 2效应细胞比Th 1细胞表现出更多的NFAT和AP-1转录活性。 在项目3中，Rincon博士将扩展这些发现，以确定a）在初始，效应Th 1和Th 2以及记忆CD 4 + T细胞中调节NFAT转录活性的机制，以及B）特定NFAT家族成员在这些CD 4 + T细胞群的活化，分化和存活中的作用。 这些研究将提供关于效应Th 1和Th 2细胞的细胞调节（项目1和2）以及从幼稚T细胞转变为记忆T细胞期间细胞因子分化的分子调节（项目3）的信息。