Development and Maintenance of Memory CD8 T Cells

描述(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因子。对广泛传播的感染，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，因为在大约6个月的时间里，由于对病毒外壳蛋白血凝素(HA)和神经氨酸酶(NA)的抗体反应减弱，以及病毒HA和NA基因的快速变化，它们必须每年重新配方。CD8T细胞在清除流感病毒中起着关键作用。与主要针对HA和NA的抗体反应相比，CD8T细胞不仅可以对来自HA和NA的表位做出反应，还可以对其他病毒蛋白产生的表位做出反应，这些表位的变化不像HA和NA那么快。诱导CD8 T细胞对更保守的病毒成分产生反应的疫苗将提供当前疫苗的替代方案，并可能消除每年重新配制疫苗的需要。然而，诱导记忆性CD8 T细胞的疫苗的开发一直具有挑战性，部分原因是对记忆性CD8 T细胞的发育和维护缺乏了解。我们开发了一种流感病毒感染的过继转移模型，在该模型中，抗原特异性CD8T细胞可以在任何时间和任何解剖位置被跟踪。利用该系统，我们建议研究与流感病毒的记忆性CD8 T细胞发育和维持相关的关键问题。具体地说，将研究干扰素-γ调节效应CD8T细胞收缩的细胞和分子机制。流感感染后，肺内记忆CD8 T细胞迅速消失的原因将被确定。将开发一种有效的慢病毒介导的基因转移来研究记忆CD8 T细胞发育和维持中的基因功能。预计这些研究结果将有助于促进对免疫记忆的基本了解，并为疫苗的开发提供策略，这些疫苗可以诱导人类对流感病毒的CD8 T细胞反应。

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.