CD1 Molecules & NKT Cells in Host Defense

CD1分子

基本信息

批准号：
8044362
负责人：
Randy R Brutkiewicz
金额：
$ 34.65万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8044362
关键词：
Address Affect Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Agents Autoimmune Diseases Autoimmunity Biochemical Biological Assay CD1 Antigens Cell Communication Cells Communicable Diseases Confocal Microscopy Cytoplasmic Tail Cytoskeleton Dendritic Cells Development Dominant-Negative Mutation Exposure to Family member Future Goals Hematopoietic Hematopoietic stem cells Herpesvirus 1 Histocompatibility Antigens Class II Host Defense Immune Immune response Immune system Immunity Infection Lipids Malignant Neoplasms Mediating Molecular Mus Mutant Strains Mice Pathway interactions Protein Kinase Protein Kinase C Proteins ROCK1 gene Regulation Rho-associated kinase Role Signal Pathway Signal Transduction Pathway Signaling Molecule Testing Vaccinia virus Viral Viral Proteins Virus Virus Diseases in vivo killer T cell migration mutant pathogen rho rho GTP-Binding Proteins vaccine development

项目摘要

The regulation of the antiviral immune response is important for the elimination of a viral pathogen during a primary infection and for the development of protective immunity that will be effective upon re-exposure to that virus in the future. We and others have shown that the innate immune response, specifically, lipid antigen presentation by CD1d to natural killer T (NKT) cells, is an important component of that antiviral immune response. Recently, we demonstrated that a number of signal transduction pathways regulate antigen presentation by CD1d, as well as MHC class II molecules. We further showed that virus infections can disrupt these signaling pathways and alter the intracellular localization of CD1d as a means of immune evasion, vis-¿vis CD1d-NKT cell interactions. The CD1d cytoplasmic tail can also be phosphorylated, which can have profound effects on its functional expression. The overall goal of this competitive renewal application is to build upon our prior studies and understand in more detail the mechanisms by which CD1d-mediated antigen presentation is regulated normally and how viruses can affect the ability of cells to present antigen to NKT cells. Our hypothesis is that the Rho GTPase signaling pathway is an important regulator of antigen presentation by CD1d and viruses target Rho-dependent cytoskeletal dynamics in antigen presenting cells to impair their ability to activate NKT cells. To test this hypothesis, we have proposed three specific aims: 1. Determine the role of Rho GTPases in the control of CD1d-mediated antigen presentation; 2. Analyze the mechanism(s) by which viruses target the Rho pathway to disrupt antigen presentation by CD1d; 3. Analyze Rho GTPase-dependent CD1d and NKT cell dynamics in vivo. Increasing our understanding of the molecular mechanisms that govern antigen presentation by CD1d has applications not only in infectious diseases and vaccine development, but also in cancer and autoimmune diseases as well.

抗病毒免疫反应的调节对于消除病毒很重要原发感染期间的病原体以及保护性免疫的发展我们和其他人已经证明，在未来再次接触该病毒时会有效。免疫反应，特别是 CD1d 向自然杀伤 T (NKT) 细胞呈递脂质抗原，是抗病毒免疫反应的重要组成部分。最近，我们证明了许多信号转导途径通过 CD1d 以及 MHC 调节抗原呈递我们进一步表明，病毒感染可以破坏这些信号传导。途径并改变 CD1d 的细胞内定位作为免疫逃避的手段，vis-¿可见 CD1d-NKT 细胞相互作用 CD1d 胞质尾部也可以被磷酸化。可以对其功能表达产生深远的影响。续签申请是建立在我们之前的研究的基础上，并更详细地了解 CD1d 介导的抗原呈递正常调节的机制以及如何病毒可以影响细胞向 NKT 细胞呈递抗原的能力。 Rho GTPase 信号通路是抗原呈递的重要调节因子 CD1d 和病毒在抗原呈递中以 Rho 依赖性细胞骨架动力学为目标为了检验这一假设，我们提出了对 NKT 细胞进行损伤的研究。三个具体目标： 1. 确定 Rho GTPases 在 CD1d 介导的控制中的作用 2. 分析病毒靶向 Rho 途径的机制破坏 CD1d 的抗原呈递；3. 分析 Rho GTPase 依赖性 CD1d 和 NKT 细胞增加我们对控制分子机制的理解。 CD1d 的抗原呈递不仅在传染病和疫苗中具有应用发展，而且还涉及癌症和自身免疫性疾病。