T cell function in murine gammaherpesvirus infection

鼠伽马疱疹病毒感染中的 T 细胞功能

基本信息

批准号：
8074125
负责人：
Edward J Usherwood
金额：
$ 34.59万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8074125
关键词：
Acquired Immunodeficiency Syndrome Acute Address Antigens Antiviral Agents Area Awareness Biology CD28 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Cycle Progression Cell physiology Cells Characteristics Chronic Competence Data Dendritic Cells Disease Dissection Effectiveness Environment Failure Frequencies Health Herpesviridae Infections Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Immunity Immunologic Surveillance Immunology Individual Infection Inflammatory Interleukin-2 Knowledge Licensing Lung Methods Modeling Molecular Mus Nature Patients Phenotype Play Process Production Recombinants Recrudescences Recruitment Activity Recurrence Regulation Role Signal Transduction Site System T cell response T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing Therapeutic Transgenic Organisms Tryptophan 2,3 Dioxygenase Viral Virus Virus Diseases cell transformation cell type gammaherpesvirus immunosuppressed in vivo memory CD4 T lymphocyte mouse model novel therapeutic intervention programs research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): The human gammaherpesviruses, Epstein-Barr virus and Human Herpesvirus-8, pose significant health problems in immunosuppressed individuals such as AIDS patients. Immune surveillance by antiviral T cells normally contains infected cells, however when this immune surveillance fails virus-transformed cells can outgrow and cause disease. The CD8 T cell response to gammaherpesviruses is relatively well characterized, but there is a growing appreciation that the CD4 T cell response may also play an important role in immune surveillance. However, a detailed dissection of the function and in vivo activity of gammaherpesvirus-specific CD4 T cells is not possible in human systems. Therefore we turned to a highly tractable mouse model, murine gammaherpesvirus-68, to address important questions regarding the CD4 T cell response. One significant problem which hinders the detailed study of CD4 T cell responses is that they are present at a very low frequency. Here we avoid this problem by using a system where the frequency of CD4 T cells is enlarged prior to infection, using T cell receptor transgenic CD4 T cells and recombinant MHV-68 containing the appropriate antigen. This system can then be used to track the virus-specific CD4 T cell response as the infection progresses. In Specific Aim 1 we will use this system to determine the functional and phenotypic characteristics of the CD4 T cell response in MHV-68 infection. In addition we will determine the factors necessary for sustaining the CD4 T cell response so that it can endure long-term. In Specific Aim 2 we will focus on another important role of the CD4 T cell response - licensing of dendritic cells. This CD40-dependent process is necessary for the transmission of CD4 T cell 'help' to the CD8 T cell response. In this aim we will determine how the biology of dendritic cells changes in the presence or absence of CD40, to understand licensing during MHV-68 infection on a molecular level. Our third Specific Aim focuses on the mechanism behind the loss of control of MHV-68 infection in mice deficient in T cell help. Our preliminary data detail a method of re-establishing control of MHV-68 infection in CD40-deficient mice, where the virus spontaneously reactivates in the lungs. Therefore this section proposes to understand the precise mechanism behind this effect, which may have important therapeutic benefit in AIDS patients suffering from disease caused by recurrent gammaherpesvirus infection.

描述（由申请人提供）：人类伽马病毒，爱泼斯坦 - 巴尔病毒和人类疱疹病毒8，在诸如艾滋病患者等免疫抑制的个体中构成了重大健康问题。抗病毒T细胞的免疫监视通常包含感染的细胞，但是当这种免疫监测失败时，病毒转换的细胞可能会产生并引起疾病。 CD8 T细胞对γ掌病毒的反应相对很好地表征，但是人们越来越多地认为CD4 T细胞反应在免疫监测中也可能起重要作用。然而，在人类系统中，不可能详细的解剖和体内活性。因此，我们转向了高度可牵引的小鼠模型，鼠γ瘤病毒-68，以解决有关CD4 T细胞响应的重要问题。阻碍CD4 T细胞反应的详细研究的一个重要问题是它们以非常低的频率存在。在这里，我们通过使用在感染前将CD4 T细胞频率扩大的系统避免了此问题，使用T细胞受体转基因CD4 T细胞和含有适当抗原的重组MHV-68。然后，随着感染的进行，该系统可用于跟踪病毒特异性的CD4 T细胞反应。在特定目标1中，我们将使用该系统来确定MHV-68感染中CD4 T细胞反应的功能和表型特性。此外，我们将确定维持CD4 T细胞反应所需的因素，以便它可以长期忍受。在特定目标2中，我们将重点介绍CD4 T细胞反应的另一个重要作用 - 树突状细胞的许可。 CD40依赖性过程对于将CD4 T细胞“帮助”传输到CD8 T细胞响应中是必需的。在此目标中，我们将确定树突状细胞的生物学在存在或不存在CD40的情况下如何变化，以了解分子水平MHV-68感染期间的许可。我们的第三个特定目的集中于失去缺乏T细胞帮助小鼠MHV-68感染的控制的机制。我们的初步数据详细介绍了一种重新建立CD40缺陷小鼠中MHV-68感染的方法，该病毒在肺中自发反应。因此，本节提议了解这种作用背后的确切机制，这可能对因复发性γ鞘病毒感染而引起的疾病患者具有重要的治疗益处。