Development and Maintenance of Memory CD8 T Cells

记忆 CD8 T 细胞的发育和维护

基本信息

批准号：
7658904
负责人：
Jianzhu Chen
金额：
$ 38.69万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7658904
关键词：
Adoptive Transfer Antibody Formation Antigens B-Lymphocytes Bioterrorism CD8B1 gene Capsid Proteins Cell Death Cells Development Epitopes Gene Deletion Gene Expression Gene Transfer Genes Human Immunity Immunologic Memory In Situ Infection Influenza Influenza A virus Interferon Type II Interleukin 7 Receptor Interleukin-15 Interleukin-7 Intervention Location Lung Lymphoid Maintenance Mediating Medical Memory Modeling Molecular Mus Neuraminidase Organ Physiological Play Prevention Process Public Health Regulation Research Personnel Role Source Subfamily lentivirinae System T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Testing Time Transgenes Vaccination Vaccines Viral Viral Proteins Viral Vector Virus Diseases base cost cost effective cytokine effective intervention gene function influenza virus vaccine influenzavirus interleukin-15 receptor prevent programs receptor expression response vaccine development

项目摘要

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.

描述（由申请人提供）：流感病毒是一个主要的公共卫生问题，也是潜在的致命生物恐怖主义。诸如流感等广泛差异感染的最具成本效益的干预是通过预防疫苗接种。然而，当前流感疫苗的价值受到限制，因为由于六个月内，由于对病毒涂层蛋白的血凝素（HA）和神经氨基酶（NA）的抗体反应的减弱，必须每年重新校正，并且病毒HA和Na基因的快速变化。 CD8 T细胞在清除流感病毒中起关键作用。与主要针对HA和Na的抗体反应相比，CD8 T细胞不仅可以响应不仅HA和NA的表位，而且还可以响应其他病毒蛋白，而其他病毒蛋白的变化不如HA和Na。诱导CD8 T细胞对更保守的病毒成分反应的疫苗将为当前的疫苗提供替代方案，并可能消除对年度重新制定的需求。但是，诱导记忆CD8 T细胞的疫苗的开发一直在挑战，部分原因是对记忆CD8 T细胞的发育和维护缺乏了解。我们已经开发了一种流感病毒感染的收养转移模型，在该模型中，可以随时且在任何解剖位置遵循抗原特异性CD8 T细胞。使用该系统，我们建议研究与记忆CD8 T细胞开发和与流感病毒保持有关的关键问题。具体而言，将研究IFN-GAMMA调节效应CD8 T细胞收缩的细胞和分子机制。将确定流感感染后肺中记忆CD8 T细胞快速消失的原因。将开发有效的慢病毒介导的基因转移，以研究记忆CD8 T细胞发育和维持中的基因功能。可以预料，提出的研究的发现将有助于进步对免疫记忆的基本理解，并为开发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。