Direct Regulation of CD8 T Cells by Interferon gamma

干扰素 γ 对 CD8 T 细胞的直接调节

• 批准号: 7878289
• 负责人: Marulasiddappa Suresh
• 金额: $ 0.89万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-14 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878289
• 关键词: Address; Affect; Antibody Formation; Antigens; Area; Arenaviridae; Arenavirus; Biological Warfare; Bioterrorism; Blocking Antibodies; Bone Marrow; CD8B1 gene; Categories; Cell Lineage; Cellular Immunity; Data; Development; Dominant-Negative Mutation; Effectiveness; Effector Cell; Exhibits; Filovirus; Flavivirus; Human; Human Virus; Immunity; Immunotherapeutic agent; Impairment; Infection; Interferon Type II; Interferons; Investigation; Lassa virus; Lymphocytic choriomeningitis virus; MHC Class I Genes; Mediating; Memory; Modality; Modeling; Morbidity - disease rate; Mus; Old World Arenaviruses; Orthobunyavirus; Phase; Play; Regulation; Rodent; Role; Seminal; Signal Transduction; T memory cell; T-Lymphocyte; Tacaribe Complex Viruses; Tacaribe virus; Time; Transgenic Mice; Transgenic Organisms; Vaccination; Vaccines; Viral Hemorrhagic Fevers; Virus; Virus Diseases; base; cytotoxic; in vivo; insight; mortality; mouse model; pathogen; prototype; receptor; research study; response; vaccine development

DESCRIPTION (provided by applicant): Arena viruses are one of the many etiologic agents of viral hemorrhagic fever (VHF) in humans. Because of the high rates of mortality and morbidity associated with these infections, and the potential of being used as agents of bioterrorism, are arenaviruses are classified under category A pathogens. At the present time, there are no vaccines to provide protection against arena viral infections in human beings. The Old World arena viruses include the Lassa virus and lymphocytic choriomeningitis virus (LCMV). Evidence indicate that cellular immunity mediated by CD8 T cells is important in defense against LCMV, and most likely Lassa virus. Therefore, vaccines against these viruses need to engender potent CD8 T cell memory. However, the mechanism(s) of induction of CD8 T cell memory are not well understood and currently, this is an area of intense investigation. Typically, CD8 T cell responses can be divided into three distinct phases: (1) the expansion phase when naive T cells undergo antigen-driven proliferation and differentiation into effector cells, (2) the contraction phase when 90-95% of the expanded T cells are eliminated, and (3) the memory phase when the remaining 5% of the expanded CD8 T cells survive for extended periods as memory T cells. The number of memory CD8 T cells generated is dependent upon the extent of expansion and the magnitude of contraction. Since protective immunity is dependent upon the induction of a threshold number of memory CD8 T cells, it is critical to gain a thorough understanding of the mechanisms that regulate the expansion and contraction phases of the T cell response. Using the well-characterized LCMV model in mice, we have obtained strong preliminary data that IFNgamma receptor (IFNgammaR) signaling plays an important role in limiting the number of antigen-specific memory CD8 T cells that survive the contraction phase of the T cell response. Based on this a strong case can be made to modulate IFNgammaR signaling to augment the number of memory CD8 T cells during vaccination. Understanding the mechanisms underlying the regulation of LCMV-specific CD8 T cell response by IFNgammaR is the focus of this proposal. The specific aims are: (1) To determine the importance of IFNgammaR expressed on T cells vs. non-T cells in regulating CD8 T cell responses in vivo by utilizing TCR transgenic mice, bone marrow chimeric mice, and IFN( unresponsive transgenic T cells, (2) To investigate the importance of temporal and spatial control of IFNgammaR signaling in the regulation of the contraction phase of LCMV-specific CD8 T cell response by antibody blocking experiments and by developing a transgenic mouse model in which IFNgammaR expression in T-cell lineage can be turned on and off at will, and (3) To determine the effect of IFNgammaR deficiency on the qualitative and functional attributes of LCMV-specific memory CD8 T cells. These studies should aid in the development of vaccines against arena viruses in particular and other viruses in general.

描述（由申请人提供）：沙粒病毒是人类病毒性出血热（VHF）的多种病原体之一。由于与这些感染相关的高死亡率和发病率，以及被用作生物恐怖主义媒介的潜力，沙粒病毒被归类为 A 类病原体。目前，还没有疫苗可以针对人类沙粒病毒感染提供保护。旧世界竞技场病毒包括拉沙病毒和淋巴细胞脉络膜脑膜炎病毒（LCMV）。有证据表明，CD8 T 细胞介导的细胞免疫对于防御 LCMV（最有可能是拉沙病毒）非常重要。因此，针对这些病毒的疫苗需要产生有效的 CD8 T 细胞记忆。然而，诱导 CD8 T 细胞记忆的机制尚不清楚，目前这是一个深入研究的领域。通常，CD8 T 细胞反应可分为三个不同的阶段：(1) 扩增阶段，此时幼稚 T 细胞经历抗原驱动的增殖并分化为效应细胞，(2) 收缩阶段，此时 90-95% 的扩增 T 细胞(3) 记忆阶段，剩余 5% 的扩增 CD8 T 细胞作为记忆 T 细胞存活较长时间。产生的记忆 CD8 T 细胞的数量取决于扩张的程度和收缩的幅度。由于保护性免疫依赖于诱导阈值数量的记忆 CD8 T 细胞，因此彻底了解调节 T 细胞反应的扩张和收缩阶段的机制至关重要。使用小鼠中充分表征的 LCMV 模型，我们获得了强有力的初步数据，表明 IFNgamma 受体 (IFNgammaR) 信号在限制 T 细胞反应收缩期存活的抗原特异性记忆 CD8 T 细胞的数量方面发挥着重要作用。基于此，可以有力地证明在疫苗接种过程中调节 IFNgammaR 信号传导以增加记忆 CD8 T 细胞的数量。了解 IFNgammaR 调节 LCMV 特异性 CD8 T 细胞反应的机制是本提案的重点。具体目标是：（1）利用TCR转基因小鼠、骨髓嵌合小鼠和IFN（无反应性转基因T细胞）确定T细胞相对于非T细胞表达的IFNγR在调节体内CD8 T细胞反应中的重要性。 , (2) 通过抗体阻断实验和开发转基因小鼠模型，研究 IFNgammaR 信号传导的时间和空间控制在调节 LCMV 特异性 CD8 T 细胞反应收缩期的重要性。 T 细胞谱系中的 IFNgammaR 表达可以随意打开和关闭，并且 (3) 确定 IFNgammaR 缺陷对 LCMV 特异性记忆 CD8 T 细胞的质量和功能属性的影响。特别是针对沙粒病毒和一般其他病毒的疫苗。