Direct Regulation of CD8 T Cells by Interferon gamma

描述(申请人提供)：竞技场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致残率，以及被用作生物恐怖主义因素的可能性，阿拉伯病毒被归类为A类病原体。目前，还没有针对人类竞技场病毒感染提供保护的疫苗。旧大陆的竞技场病毒包括拉萨病毒和淋巴细胞性脉络膜脑膜炎病毒(LCMV)。有证据表明，CD8T细胞介导的细胞免疫在抵御LCMV和最有可能的Lassa病毒方面具有重要作用。因此，针对这些病毒的疫苗需要产生强大的CD8 T细胞记忆。然而，对CD8T细胞记忆的诱导机制(S)还不是很清楚，目前，这是一个正在加紧研究的领域。典型的CD8T细胞反应可分为三个不同的阶段：(1)扩增阶段，当原始T细胞经历抗原驱动的增殖和分化为效应细胞；(2)收缩阶段，当90%-95%的扩增的T细胞被消除；(3)记忆阶段，当剩余的5%的扩增的CD8T细胞作为记忆T细胞存活更长的时间。产生的CD8记忆T细胞的数量取决于扩张的程度和收缩的程度。由于保护性免疫依赖于一定数量的记忆CD8 T细胞的诱导，因此彻底了解调节T细胞反应的扩张和收缩阶段的机制是至关重要的。利用小鼠的LCMV模型，我们已经获得了强有力的初步数据，即IFNGamma受体(IFNGammaR)信号在限制T细胞反应的收缩阶段存活的抗原特异性记忆CD8T细胞的数量方面发挥着重要作用。基于这一点，可以提出一个强有力的理由来调节IFNGammaR信号，以在疫苗接种期间增加CD8记忆T细胞的数量。了解IFNGammaR调节LCMV特异性CD8 T细胞反应的潜在机制是这项提议的重点。其具体目的是：(1)利用TCR转基因小鼠、骨髓嵌合小鼠和无应答转基因T细胞，确定T细胞和非T细胞上表达的IFNGammaR在体内调节CD8 T细胞反应中的重要性；(2)通过抗体阻断实验和建立T细胞系中IFNGammaR表达可随意开启和关闭的转基因小鼠模型，研究IFNGammaR信号在调节LCMV特异性CD8 T细胞反应收缩阶段中的时间和空间控制的重要性。以及(3)确定IFNGammaR缺陷对LCMV特异性记忆CD8T细胞的性质和功能的影响。这些研究应有助于开发针对竞技场病毒和一般其他病毒的疫苗。

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.