Gene expression in non-functional CD8 T cells

非功能性 CD8 T 细胞中的基因表达

• 批准号: 6891394
• 负责人: SALLY R. SARAWAR
• 金额: $ 27.3万
• 依托单位: TORREY PINES INST FOR MOLECULAR STUDIES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6891394
• 关键词: CD40 molecule; Epstein Barr virus; Herpesviridae; Herpesviridae disease; MHC class II antigen; antigen antibody reaction; cellular immunity; cytotoxic T lymphocyte; diagnostic respiratory lavage; disease /disorder model; flow cytometry; gene expression; genetically modified animals; helper T lymphocyte; human herpesvirus 8; immune response; immunofluorescence technique; immunogenetics; laboratory mouse; latent virus infection; microarray technology; opportunistic infections; polymerase chain reaction; virus infection mechanism; virus replication

DESCRIPTION (provided by applicant): Reactivation of latent herpesviruses is a particular problem in immunocompromised individuals such as AIDS patients who lack effective CD4 T helper cell function. Infection of mice with murine gammaherpesvirus-68 (MHV-68), which is closely related to the human pathogens Epstein Barr virus and Kaposi's sarcoma associated herpesvirus, provides a useful small animal model for studying the immune response to gamma herpesviruses and for testing the ability of potential immunotherapeutic agents to control viral reactivation. CD4 T cell deficient mice can clear an initial challenge with MHV-68, but fail to control latent virus, which later reactivates in the lungs. Using this mouse model of opportunistic infection, we showed that agonistic antibodies to CD40 could substitute for CD4 T cell function in preventing the reactivation of MHV-68 in CD4 T cell deficient mice. Our data also showed that CD8+ T cells were required for this effect. However, no difference in the number or cytolytic activity of CD8 cells was detected. In the linked application, experiments in Aim 1 were directed at determining whether anti-CD40 antibody treatment induced a direct change in the function of the CD8 T cells or acted at another essential step in the control of viral reactivation, without affecting CD8 T cell function. We have now obtained new data from adoptive transfer experiments, which show that anti-CD40 treatment induces a direct change in CD8 T cell function, enabling the control of viral reactivation. Hence we now have the justification to carry out more extensive studies to determine exactly how the CD8 T cells differ in anti-CD40 and control antibody-treated CD4 T cell-deficient mice during MHV-68 infection. In the current R21 application, we propose use gene microarrays to determine how gene expression differs in these functional and non-functional CD8 T cells. These studies are consistent with the exploratory nature of the R21 mechanism of support and the application of microarray technology is specifically cited in the Program announcement. We anticipate that the analyses will reveal differences in the expression of key regulatory or effector molecules. This will give us an insight into how CD8 T cell function is altered by the anti-CD40 antibody treatment or CD4 T cell help (mediated by CD40L) and what characteristics define a functional CD8 T cell. These studies will both extend and complement studies in the linked R01. The data are likely to lead to a new understanding of how CD8 T cells function in the control of persistent viral infections and mechanisms of CD8 T cell activation.

描述（由申请人提供）：潜伏疱疹病毒的再活化是免疫功能低下个体（如缺乏有效CD 4 T辅助细胞功能的AIDS患者）的一个特殊问题。小鼠γ疱疹病毒-68（MHV-68）与人类病原体Epstein巴尔病毒和卡波西肉瘤相关疱疹病毒密切相关，其感染小鼠为研究对γ疱疹病毒的免疫应答和测试潜在免疫抑制剂控制病毒再活化的能力提供了有用的小动物模型。CD 4 T细胞缺陷小鼠可以清除MHV-68的初始攻击，但无法控制潜伏病毒，后者随后在肺部重新激活。使用这种机会性感染的小鼠模型，我们表明CD 40的激动性抗体可以替代CD 4 T细胞功能，防止CD 4 T细胞缺陷小鼠中MHV-68的再活化。我们的数据还表明，这种效应需要CD 8 + T细胞。然而，未检测到CD 8细胞的数量或细胞溶解活性的差异。在相关申请中，目的1中的实验旨在确定抗CD 40抗体处理是否诱导CD 8 T细胞功能的直接变化或在控制病毒再活化的另一个必要步骤中起作用，而不影响CD 8 T细胞功能。我们现在已经从过继转移实验中获得了新的数据，这些数据表明抗CD 40治疗诱导了CD 8 T细胞功能的直接变化，从而能够控制病毒的再活化。因此，我们现在有理由进行更广泛的研究，以确定在MHV-68感染期间，抗CD 40和对照抗体处理的CD 4 T细胞缺陷小鼠中CD 8 T细胞的确切差异。在目前的R21应用中，我们建议使用基因微阵列来确定这些功能性和非功能性CD 8 T细胞中基因表达的差异。这些研究与R21支持机制的探索性质一致，并且在计划公告中特别引用了微阵列技术的应用。我们预计，这些分析将揭示关键调控或效应分子表达的差异。这将使我们深入了解抗CD 40抗体治疗或CD 4 T细胞帮助（由CD 40 L介导）如何改变CD 8 T细胞功能，以及功能性CD 8 T细胞的特征。这些研究将扩展和补充相关R 01中的研究。这些数据可能会导致对CD 8 T细胞如何在控制持续性病毒感染和CD 8 T细胞活化机制中发挥作用的新理解。