Activation of NKT cells by cytomegalovirus

巨细胞病毒激活 NKT 细胞

基本信息

批准号：
7842640
负责人：
CHRISTOPHER A BENEDICT
金额：
$ 23.61万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842640
关键词：
Acquired Immunodeficiency Syndrome Acute Affect Agonist Animals Antibodies Antigen Presentation Antigens Antiviral Agents Applications Grants Autoantigens Bacteria Blocking Antibodies Cell Culture Techniques Cells Coculture Techniques Complex Congenital Abnormality Cytomegalovirus Cytomegalovirus Infections DNA Viruses Data Dendritic Cells Development Disease Family Gene Expression Genes Glycolipids Granulocyte-Macrophage Colony-Stimulating Factor Herpesviridae Immune Immune response In Vitro Individual Infant Mortality Infection Control Interferons Interleukin-12 Interleukin-18 Interleukin-6 Kidney Laboratories Leukocytes Life Ligands Mediating Methods Microbe Molecular Murid herpesvirus 1 Mus Natural Killer Cells Pathway interactions Peripheral Play Principal Investigator Production Public Health Role Screening procedure System T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Thymus Gland Time Tissues Viral Virus Virus Diseases adaptive immunity capsule cell type cytokine fighting follow-up in vitro Assay in vivo interleukin-12 receptor killer T cell member pathogen receptor research study response tool

项目摘要

DESCRIPTION (provided by applicant): The innate immune response to pathogens is critical for the control of infection prior to the development of adaptive immunity. NKT cells with an invariant T cell antigen receptor (TCR) 1 chain (iNKT cells) are a unique T lymphocyte subset. They have been implicated in the responses to several bacteria that have glycolipid antigens that can engage their canonical TCR. iNKT cells also have been implicated, however, in the response to diverse microbes, including viruses, which do not encode antigens for this TCR. In our preliminary studies, we have found that iNKT cells are activated in vitro to produce cytokines after culture with dendritic cells (DC) infected with mouse cytomegalovirus (MCMV, a 2-herpesvirus), and this requires TLR9, IL-12 and a particular DC subset. NK cells are critical for control of acute MCMV infection, and activated iNKT cells are known to activate NK cells. The mechanism(s) governing iNKT cell activation and their contribution to the innate control of viral infection are largely unknown. Given the tools that the laboratories of the two principal investigators have assembled, we consider MCMV infection to be an ideal system for exploring how iNKT cells are activated by DNA viruses. We will decipher the mechanism(s) required for activation of iNKT cells upon MCMV infection of DC by 1) Determining the in vivo roles of TLR9, IL-12 and CD1d-mediated antigen presentation for their activation, 2) identifying the relevant DC type(s) that activate iNKT cells after MCMV infection and 3) delineating how the relevant DC subtype stimulates iNKT cells when infected with MCMV. This exploratory proposal provides a framework for uncovering the complex molecular and cellular interplay that occurs between a viral-pathogen, DC subsets and iNKT cells, which are likely to be important in antiviral immune defense. The results obtained form these studies therefore should help in devising strategies for augmenting the response to pathogenic viruses, especially members of the herpesvirus family. PUBLIC HEALTH RELAVANCE Natural killer T (NKT) cells are a unique subset of white blood cells that help to control bacterial and viral infections. However, few specifics are known about how they fight virus infection. In this project we will study how the NKT cell and other immune cells interact to mount good antiviral defenses, using a virus that is a member of the herpesvirus family. This virus is a significant cause of infant mortality, birth defects, and disease in immune suppressed individuals, such as those with AIDS.

描述（由申请人提供）：对病原体的先天免疫反应对于在自适应免疫发展之前控制感染至关重要。具有不变T细胞抗原受体（TCR）1链（INKT细胞）的NKT细胞是独特的T淋巴细胞亚群。它们与对几种具有糖脂抗原的细菌的反应有关，这些细菌可以参与其规范的TCR。但是，inkt细胞也与对不同的微生物（包括病毒）的反应有关，这些病毒不编码该TCR的抗原。在我们的初步研究中，我们发现在体外激活Inkt细胞在用小鼠巨细胞病毒（MCMV，2-赫性病毒）感染的树突状细胞（DC）后产生细胞因子，这需要TLR9，IL-12，IL-12和特定的DC子集。 NK细胞对于控制急性MCMV感染至关重要，并且已知活化的Inkt细胞激活NK细胞。管理INKT细胞激活的机制及其对病毒感染的先天控制的贡献在很大程度上未知。鉴于两个主要研究者的实验室组装的工具，我们认为MCMV感染是探索如何被DNA病毒激活的理想系统。 We will decipher the mechanism(s) required for activation of iNKT cells upon MCMV infection of DC by 1) Determining the in vivo roles of TLR9, IL-12 and CD1d-mediated antigen presentation for their activation, 2) identifying the relevant DC type(s) that activate iNKT cells after MCMV infection and 3) delineating how the relevant DC subtype stimulates iNKT cells when infected与MCMV。该探索性建议提供了一个框架，用于揭示病毒性疾病，DC亚群和Inkt细胞之间发生的复杂分子和细胞相互作用，这些框架在抗病毒免疫防御中可能很重要。因此，这些研究获得的结果应有助于制定增强对病毒病毒的反应的策略，尤其是疱疹病毒家族的成员。公共卫生恢复天然杀伤（NKT）细胞是有助于控制细菌和病毒感染的白细胞的独特子集。但是，很少有关于它们如何抵抗病毒感染的具体细节。在这个项目中，我们将研究NKT细胞和其他免疫细胞如何使用作为疱疹病毒家族成员的病毒进行良好的抗病毒防御措施相互作用。该病毒是免疫抑制个体（例如患有艾滋病的人）中婴儿死亡率，出生缺陷和疾病的重要原因。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The mouse cytomegalovirus glycoprotein m155 inhibits CD40 expression and restricts CD4 T cell responses.

小鼠巨细胞病毒糖蛋白 m155 抑制 CD40 表达并限制 CD4 T 细胞反应。

DOI：
10.1128/jvi.02178-10
发表时间：
2011
期刊：
Journal of virology
影响因子：
5.4
作者：
Loewendorf,AndreaI;Steinbrueck,Lars;Peter,Christoph;Busche,Andreas;Benedict,ChrisA;Kay-Jackson,PenelopeC
通讯作者：
Kay-Jackson,PenelopeC

Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything.