Development and Maintenance of Memory CD8 T Cells

描述（由申请人提供）：甲型流感病毒是一个主要的公共卫生问题，也是一种潜在的致命生物恐怖主义制剂。对广泛传播的传染病（如流感）最具成本效益的干预措施是通过接种疫苗进行预防。然而，目前的流感疫苗的价值是有限的，因为它们必须每年重新配制，这是由于在大约六个月内对病毒外壳蛋白血凝素（HA）和神经氨酸酶（NA）的引发的抗体应答减弱以及病毒HA和NA基因的快速变化。CD 8 T细胞在流感病毒的清除中起关键作用。与主要靶向HA和NA的抗体应答相比，CD 8 T细胞可以应答不仅来自HA和NA而且来自其他病毒蛋白的表位，这些表位不像HA和NA那样迅速变化。诱导CD 8 T细胞对更保守的病毒成分应答的疫苗将为目前的疫苗提供替代方案，并可能消除每年重新配制的需要。然而，诱导记忆性CD 8 T细胞的疫苗的开发一直具有挑战性，部分原因是缺乏对记忆性CD 8 T细胞发育和维持的理解。我们已经开发了一种流感病毒感染的过继转移模型，其中抗原特异性CD 8 T细胞可以在任何时间和任何解剖位置进行追踪。使用这个系统，我们建议调查的关键问题，是相关的记忆CD 8 T细胞的发展和维护流感病毒。具体而言，将研究IFN-γ调节效应CD 8 T细胞收缩的细胞和分子机制。将确定流感感染后肺部记忆性CD 8 T细胞快速消失的原因。将开发一种有效的慢病毒介导的基因转移来研究记忆性CD 8 T细胞发育和维持中的基因功能。预计拟议研究的结果将有助于促进对免疫记忆的基本理解，并为开发可诱导人类对流感病毒的CD 8 T细胞应答的疫苗提供策略。

DESCRIPTION (provided by applicant): Influenza A virus is a major public health problem and a potentially lethal bioterrorism agent. The most cost- effective intervention for a wide spread infection, such as influenza, is through prevention by vaccination. However, the value of current influenza vaccines is limited because they have to be reformulated every year due to waning of the elicited antibody responses to viral coat proteins hemagglutanin (HA) and neuraminidase (NA) in about six months and rapid changes of viral HA and NA genes. CD8 T cells play a critical role in clearance of influenza virus. Compared to antibody responses that are predominantly targeted to HA and NA, CD8 T cells can respond to epitopes derived from not only HA and NA but also other viral proteins, which do not change as rapidly as HA and NA. Vaccines that induce CD8 T cell responses to the more conserved viral components will provide an alternative to current vaccines and might eliminate the need for the yearly reformulation. However, development of vaccines that induce memory CD8 T cells have been challenging, partly due to a lack of understanding of memory CD8 T cell development and maintenance. We have developed an adoptive transfer model of influenza virus infection in which antigen-specific CD8 T cells can be followed at any time and in any anatomical location. Using this system, we propose to investigate key questions that are pertinent to memory CD8 T cell development and maintenance to influenza virus. Specifically, the cellular and molecular mechanisms by which IFN-gamma regulates contraction of effector CD8 T cells will be investigated. The causes underlying the rapid disappearance of memory CD8 T cells in the lung following influenza infection will be determined. An efficient lentivirus- mediated gene transfer will be developed to investigate gene function in memory CD8 T cell development and maintenance. It is anticipated that findings from the proposed studies will help to advance the basic understanding of immunological memory as well as provide strategies for the development of vaccines that can induce CD8 T cell responses to influenza virus in humans.