REGULATION OF IMMUNE RESPONSES BY VBETA SPECIFIC CD8+ T CELLS

VBETA 特异性 CD8 T 细胞对免疫反应的调节

• 批准号: 6201306
• 负责人: Leonard Chess
• 金额: $ 14.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6201306
• 关键词: CD4 molecule; CD8 molecule; T cell receptor; autoimmune disorder; autoimmunity; cell mediated cytotoxicity; cellular immunity; experimental allergic encephalomyelitis; genetically modified animals; human tissue; immunoregulation; laboratory mouse; polymerase chain reaction; superantigens

We have identified CD8+ CTL that recognize framework portions of Vbeta along with the class I-b MHC molecule Qa-1. These CD8+ cells are shown to arise in mice during the response into superantigen or after immunization of mice with activated CD4+ cells. In vitro, these CD9+ T cells kill activated CD4+ T cells in a Vbeta-specific manner. Because Qa-1 is an activation molecule on T cells and became CD9+ T cells have been shown to regulate CD4+ T cells , it is envisioned that these Qa-1 restricted, CD8 anti-Vbeta T cells serve to regulate activated CD4+ cells. This project extends the analysis of afferent mechanisms in T cell vaccination in project #2 to the study of effector mechanisms used by CD8 anti-Vbeta T cells. We will focus on animal models of autoimmunity in which CD9+ cells regulate the autoimmune process of in which defective killing by T cells contributes to t he etiology of autoimmunity. For example, animals with defects in FasL have autoimmunity and also have defects in DEB-mediated, Vbeta-specific T cell deletion, phenomenon associated with the CD8 anti- Vbeta response. In this project, we will directly investigate mechanisms whereby CD8 antiVbeta cells kill and extend these studies to the Fas/FasL system to determine whether defects in CD8-mediated killing contribute to the autoimmune syndrome exhibited by Fas and FasL mutant mice. CD8+ T cells have also been shown in the EAE model, to regulate disease and prevent relapse. We will directly study effector mechanisms used buy CD8+ T cells to regulate encephalitogenic T cells in EAE. Will determine if CD8 anti-Vbeta T cells distinguish between TH subsets and if CD9+ T cell regulation in EAE accounts for the observation that, during remission, there is a skewing of the immune response towards a TH2 phenotype. Lastly, we have hypothesized that CD8 anti-Vbeta cells specifically participate in vivo in the regulation of EAE. As a direct test of this hypothesis we will identify TCR signatures expressed by CT8 anti-Vbeta8 T cells and use these signatures to follow the expansion of this population of CD8+ cells first after immunization of mice with Vbeta9+CD4+ cells and, most importantly, during EAE. Our ability to identify these CD8+ T cells in vivo during EAE would implicate CD8 and anti-Vbeta cells as an effector CD9+ population responsible for regulating EAE.

我们已经确定了识别vbeta框架部分的CD8+ CTL 与I-B类MHC分子QA-1一起。 这些CD8+细胞显示为 在对超抗原的反应期间或免疫后出现的小鼠出现 具有活化CD4+细胞的小鼠。 在体外，这些CD9+ T细胞杀死 激活的CD4+ T细胞以VBETA特异性方式。 因为QA-1是 T细胞上的激活分子已显示为CD9+ T细胞 调节CD4+ T细胞，可以预见，这些QA-1受限制，CD8 抗VBETA T细胞用于调节活化的CD4+细胞。 这个项目 扩展对T细胞疫苗接种中传入机制的分析 CD8抗Vbeta T的效应机制研究的项目2 细胞。 我们将专注于自身免疫的动物模型，其中CD9+细胞的动物模型 调节自身免疫过程，其中T细胞有缺陷杀死 有助于自身免疫的病因。 例如，具有 FASL缺陷具有自身免疫性，并且在DEB介导的缺陷， VBETA特异性T细胞缺失，与CD8抗的现象 VBETA响应。 在这个项目中，我们将直接调查机制 CD8抗杀菌细胞杀死并将这些研究扩展到FAS/FASL 确定CD8介导的杀戮中缺陷的系统是否有助于 FA和FASL突变小鼠表现出的自身免疫性综合征。 CD8+ t 细胞也已在EAE模型中显示，以调节疾病和 防止复发。 我们将直接研究使用的效应器机制购买CD8+ T细胞调节EAE中的脑源性T细胞。 将确定CD8是否 抗VBETA T细胞区分TH子集和IF CD9+ T细胞 EAE中的法规说明了以下观察结果，即在缓解期间 对Th2表型的免疫反应偏斜。 最后， 我们假设CD8抗VBETA细胞专门参与 EAE调节中的体内。 作为对此假设的直接检验，我们将 识别CT8抗VBETA8 T细胞表达的TCR特征并使用这些 首先关注CD8+细胞种群扩展的签名 用VBETA9+ CD4+细胞对小鼠进行免疫后，最重要的是 在EAE期间。 我们在EAE期间在体内识别这些CD8+ T细胞的能力 将CD8和抗VBETA细胞作为效应子CD9+种群 负责监管EAE。