CDI Molecules & NKT Cells in Host Defense

CDI分子

• 批准号: 7088973
• 负责人: Randy R Brutkiewicz
• 金额: $ 28.7万
• 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/7088973
• 关键词: Adenoviridae; CD1 molecule; Vesiculovirus; antigen presentation; genetically modified animals; host organism interaction; human immunodeficiency virus 1; immunopathology; laboratory mouse; ligands; microorganism immunology; natural killer cells; virus cytopathogenic effect; virus diseases; virus infection mechanism

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现抗原的细胞与负责对宿主防御这些外国侵略者辩护的效应函数的细胞之间的复杂相互作用。 我们的实验室集中于主要的组织相容性复合物类分子，CD1D与抗病毒免疫中CD1D，NKT细胞激活的T细胞的独特群体之间的相互作用。我们发现，急性病毒感染后CD1D分子和NKT细胞都存在改变，可能是相关（甚至是独立）事件的。各种病毒编码的免疫逃避分子（VEIMS），例如来自HIV-1的NEF分子和腺病毒的E19分子可以与CD1D的细胞表面水平结合并大大降低。这会导致NKT细胞活化的降低，并且很可能由其他效应细胞介导的下游免疫作用。因此，病毒病原体可以在宿主中建立立足点的一种手段是针对先天性抗病毒免疫反应，而不是CD1D分子和/或NKT细胞。病毒感染后，肝脏和其他器官的NKT细胞有选择性丧失，而在CD1D1缺陷型小鼠中，病毒感染会导致更高水平的细胞因子产生和更快的病毒清除率。这表明对抗病毒免疫反应大小的控制是CD1D1依赖性的。这种竞争性更新应用的总体目标是进一步了解CD1D分子和NKT细胞在我们先前的研究基础上通过构建抗病毒免疫的作用。因此，我们的假设是，某些病毒通过与VEIMS的直接相互作用和/或通过改变NKT细胞的CD1D1依赖性激活而导致CD1D分子的功能表达降低。为了检验这一假设，我们专注于三个特定目标。 1。分析VSV抑制CDID介导的抗原表现的机制，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细胞变化的动力学。我们对CD1D分子和NKT细胞在先天抗病毒免疫反应中发挥作用的作用的理解将使我们能够利用该系统来生成新的和新型的疫苗，并且不仅对该区域，而且对自身免疫性和癌症都有明确的翻译应用。