MHC Class I Antigen Presentation in Viral Infections

病毒感染中 MHC I 类抗原呈递

基本信息

批准号：
8072956
负责人：
Luis J Sigal
金额：
$ 1.07万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072956
关键词：
Abbreviations Accounting Acute Disease Address Affect Amino Acids Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Antiviral Response Binding Blood Blood Circulation Bone Marrow CD8-Positive T-Lymphocytes CD8B1 gene Cell surface Cells Cessation of life Characteristics Chickens Complex Cross Presentation Cross-Priming Dendritic Cells Endoplasmic Reticulum Epitopes Funding Glycoproteins Goals Granulocyte-Macrophage Colony-Stimulating Factor Heat shock proteins Heating Histocompatibility Antigens Class I Home environment Homing Immune Infection Interferons Intravenous Invaded Lymphocytic choriomeningitis virus Lymphoid MHC Class I Genes Major Histocompatibility Complex Memory Modeling Molecular Mouse Pox Virus Mus Nucleoproteins Organ Orthopoxvirus Ovalbumin Ovum Pathogenesis Peptide/MHC Complex Peptides Population Proliferating Proteins Publishing Research Personnel Role Route SELL gene Secondary to Signal Transduction Spleen System T cell response T memory cell T-Cell Receptor T-Lymphocyte Testing Time Tissues Vaccinia virus Viral Virus Virus Diseases Work beta-Galactosidase cell motility cell type experience flexibility flu in vivo influenzavirus intraperitoneal long term memory lymph nodes macrophage programs research study response secondary infection subcutaneous

项目摘要

We have previously shown that bone marrow-derived professional antigen presenting cells (pAPC) are essential to prime CD8+ T cell responses against several viruses. However, the cell types and mechanisms whereby these anti-viral responses are primed are still unsolved. The current model, mostly inferred from experiments with non-infectious antigens (Ags), proposes that dendritic cells carry Ags from infected tissues to secondary lymphoid organs (SLO) where CD8+ T cells are primed. We think that this model is too simplistic and cannot account for the priming of all anti-viral CD8+ T cell responses. Furthermore, this model does not address whether the pAPC in the infected tissues must become infected with the virus and migrate thereafter to directly prime the responses, or whether it must avoid its own infection and acquire the viral Ags from other infected cells in order to maintain its migratory capacity. In this case cross-presentation could be the major mechanism involved in priming. Another possibility is that pAPC may not need to transport viral Ags to SLO but become infected or acquire the viral Ags when they are already in the SLO. In this scenario, uninfected pAPC in the tissues could sense infection, and rapidly migrate to SLO to wait for the arrival of the virus. Our hypothesis is that, in order to minimize immune evasion, Ag presentation is a flexible system that could use any of these mechanisms in order to adapt to the type of invading virus and the route of infection. In this project we will test this hypothesis using VACV and LCMV as our model viruses with the following specific Aims: Specific Aim 1: To determine and compare the ability of macrophages and DC to migrate to secondary lymphoid organs during viral infections. Specific Aim 2: To determine the ability of macrophages and DC to prime and cross-prime anti-viral naive CD8+ T cells in vivo. Specific Aim 3: To determine the role of bone marrow-derived pAPC in the activation of memory CD8+ T cells. These experiments should provide important information to understand the pathogenesis of viral infections and the induction of anti-viral CD8+ T cell responses.

我们以前已经表明，骨髓来源的专业抗原呈递细胞（PAPC）是对几种病毒的主要CD8+ T细胞反应必不可少的。但是，细胞类型和机制这些抗病毒反应的启动仍未解决。当前模型，主要是从非感染抗原（AGS）的实验提出，树突状细胞携带感染组织的AG 到启动CD8+ T细胞的继发性淋巴器官（SLO）。我们认为这个模型也是简单化，无法说明所有抗病毒CD8+ T细胞反应的启动。此外，这个模型没有解决感染组织中的PAPC是否必须感染病毒并迁移此后，要直接提出反应，或者必须避免自己的感染并获得病毒AGS 从其他受感染的细胞中维持其迁徙能力。在这种情况下，交叉表现可能是涉及启动的主要机制。另一种可能性是PAPC可能不需要运输病毒 AGS到SLO但在SLO中被感染或获得病毒AG。在这种情况下，组织中未感染的PAPC可以感染感染，并迅速迁移到SLO等待病毒。我们的假设是，为了最大程度地减少免疫逃避，AG表现是一个灵活的系统，可以使用这些机制中的任何一种来适应入侵病毒的类型和感染途径。在这个项目中，我们将使用VACV和LCMV作为我们的模型病毒检验该假设，具体目的：特定目的1：确定和比较巨噬细胞和直流迁移到次级的能力病毒感染期间淋巴器官。特定目的2：确定巨噬细胞和直流质和跨发病毒天真的能力 CD8+ T细胞体内。特定目的3：确定骨髓衍生的PAPC在存储器CD8+ T激活中的作用细胞。这些实验应提供重要信息以了解病毒感染的发病机理以及抗病毒CD8+ T细胞反应的诱导。