CDI Molecules & NKT Cells in Host Defense

CDI分子

• 批准号: 7590359
• 负责人: Randy R Brutkiewicz
• 金额: $ 27.34万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590359
• 关键词: Acute; Adenoviruses; Antigen Presentation; Antigen-Presenting Cells; Antiviral Agents; Area; Autoimmunity; Binding; Cell surface; Cells; Complex; Effector Cell; Event; Generations; Goals; HIV-1; Hepatocyte; Host Defense; Human; Immune; Immune response; Immunity; In Vitro; Laboratories; Link; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Mus; Organ; Play; Population; Production; Research Personnel; Role; System; T-Lymphocyte; Testing; Time; Vesicular stomatitis Indiana virus; Viral; Virus; Virus Diseases; cytokine; glycosylation; in vivo; multiple myeloma M Protein; mutant; novel vaccines; pathogen; programs; protein function; research study; trafficking

DESCRIPTION (provided by applicant): The immune response to pathogens involves a complex interplay between cells that present antigen and those cells that are responsible for effector functions involved in the defense of the host against these foreign invaders. Our laboratory is focused on the interactions between the major histocompatibility complex class Hike molecule, CD1d and a unique population of T cells that are activated by CD1d, NKT cells, in antiviral immunity. We have found that there are alterations in both CD1d molecules and NKT cells following an acute virus infection that may be related (or even independent) events. Various virus-encoded immune evasion molecules (VEIMs), such as the Nef molecule from HIV-1 and the E19 molecule from adenovirus can bind to and substantially decrease the cell surface level of CD1d. This results in a decrease in NKT cell activation and very likely downstream immune effects mediated by other effector cells. Thus, one means by which a viral pathogen could establish a foothold in a host is by targeting the innate antiviral immune response vis-a-vis CD1d molecules and/or NKT cells. There is a selective loss of NKT cells from the liver and other organs following a virus infection, whereas in CD1d1-deficient mice, a virus infection results in higher levels of cytokine production and faster viral clearance. This suggests that the control of the magnitude of an antiviral immune response is CD1d1-dependent. The overall goal of this competitive renewal application is to further understand the role for CD1d molecules and NKT cells in antiviral immunity by building upon our prior studies. Thus, our hypothesis is that certain viruses cause a reduction in the functional expression of CD1d molecules by a direct interaction with VEIMs and/or by altering CD1d1-dependent activation of NKT cells. To test this hypothesis, we have focused on three specific aims. 1. Analyze the mechanisms by which VSV inhibits CDId-mediated antigen presentation, 2. Analyze the functional interaction between HIV-1 Nef and human CD1d, and 3. Study the dynamics of CD1d and NKT cell changes following a virus infection. Increasing our understanding of the roles that CD1d molecules and NKT cells play in the innate antiviral immune response will allow us to exploit this system for the generation of new and novel vaccines, and has clear translational applications to not only this area, but to autoimmunity and cancer as well.

描述（由申请人提供）：对病原体的免疫反应涉及呈递抗原的细胞和负责防御宿主抵御这些外来入侵者的效应器功能的细胞之间复杂的相互作用。 我们的实验室专注于抗病毒免疫中主要组织相容性复合物类 Hike 分子 CD1d 与由 CD1d 激活的独特 T 细胞群 NKT 细胞之间的相互作用。我们发现急性病毒感染后 CD1d 分子和 NKT 细胞都发生了变化，这些变化可能是相关的（甚至是独立的）事件。各种病毒编码的免疫逃避分子 (VEIM)，例如来自 HIV-1 的 Nef 分子和来自腺病毒的 E19 分子，可以结合并显着降低细胞表面 CD1d 的水平。这导致 NKT 细胞激活减少，很可能导致其他效应细胞介导的下游免疫效应。因此，病毒病原体在宿主体内建立立足点的一种方法是针对 CD1d 分子和/或 NKT 细胞的先天抗病毒免疫反应。病毒感染后，肝脏和其他器官中的 NKT 细胞会选择性丢失，而在 CD1d1 缺陷小鼠中，病毒感染会导致细胞因子产生水平更高，病毒清除速度更快。这表明抗病毒免疫反应强度的控制是 CD1d1 依赖性的。这项竞争性更新应用的总体目标是通过我们之前的研究进一步了解 CD1d 分子和 NKT 细胞在抗病毒免疫中的作用。因此，我们的假设是，某些病毒通过与 VEIM 直接相互作用和/或通过改变 NKT 细胞的 CD1d1 依赖性激活，导致 CD1d 分子功能表达减少。为了检验这一假设，我们重点关注三个具体目标。 1. 分析 VSV 抑制 CDId 介导的抗原呈递的机制， 2. 分析 HIV-1 Nef 和人 CD1d 之间的功能相互作用，以及 3. 研究病毒感染后 CD1d 和 NKT 细胞变化的动态。加深我们对 CD1d 分子和 NKT 细胞在先天抗病毒免疫反应中所发挥作用的了解，将使我们能够利用该系统来产生新的和新颖的疫苗，并且不仅在该领域，而且在自身免疫和免疫领域具有明确的转化应用。癌症也是如此。

项目成果

Immune evasion of the CD1d/NKT cell axis.

• DOI: 10.1016/j.coi.2018.04.021
• 发表时间: 2018-06
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Brutkiewicz RR;Yunes-Medina L;Liu J
• 通讯作者: Liu J

Cell Signaling Pathways That Regulate Antigen Presentation.

• DOI: 10.4049/jimmunol.1600460
• 发表时间: 2016-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Brutkiewicz RR

CD1d1-dependent control of the magnitude of an acute antiviral immune response.

CD1d1 依赖性控制急性抗病毒免疫反应的强度。

• DOI: 10.4049/jimmunol.172.6.3454
• 发表时间: 2004
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Roberts,TonyaJ;Lin,Yinling;Spence,PhilipM;VanKaer,Luc;Brutkiewicz,RandyR
• 通讯作者: Brutkiewicz,RandyR

Development of a quantitative cell-based intracellular ELISA for the screening of B cell hybridoma supernatants: a novel rapid assay to detect positive clones.

开发用于筛选 B 细胞杂交瘤上清液的基于细胞的定量细胞内 ELISA：一种检测阳性克隆的新型快速测定法。

• DOI: 10.1089/hyb.2004.23.373
• 发表时间: 2004
• 期刊: Hybridoma and hybridomics.
• 作者: Renukaradhya,JGourapura;Sriram,Venkataraman;Polakova,Katarina;Russ,Gustav;Brutkiewicz,RandyR
• 通讯作者: Brutkiewicz,RandyR

Generation of cellular immunity to lymphocytic choriomeningitis virus is independent of CD1d1 expression.

针对淋巴细胞性脉络膜脑膜炎病毒的细胞免疫的产生不依赖于 CD1d1 的表达。

• DOI: 10.1046/j.1365-2567.2001.01302.x
• 发表时间: 2001
• 期刊: Immunology
• 影响因子: 6.4
• 作者: Spence,PM;Sriram,V;VanKaer,L;Hobbs,JA;Brutkiewicz,RR
• 通讯作者: Brutkiewicz,RR