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Dendritic cell regulation of CD8+ T cell responses

CD8 T 细胞反应的树突状细胞调节

基本信息

批准号：
7386756
负责人：
PETER D KATSIKIS
金额：
$ 34.88万
依托单位：
DREXEL UNIVERSITY
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 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386756
关键词：
Address Adjuvant Affect Animals Antigen-Presenting Cells Antigens Antiviral Agents Biological Assay CD28 Antigens CD28 gene CD8B1 gene Cells Characteristics Chemotactic Factors Complement Complement 5a Data Dendritic Cells Development Diphtheria Toxin Doctor of Medicine Doctor of Philosophy Generations Goals ITGAX gene Immune Immune response Immune system Immunity Infection Influenza Influenza A virus Lead Lung MHC Class I Genes Maintenance Mediating Memory Mus Natural Immunity Pathway interactions Peptides Phase Play Regulation Reporting Research Personnel Role Role playing therapy Signal Transduction Staging Staining method Stains T-Lymphocyte Technology Time Transgenic Animals Vaccines Viral Virus Virus Diseases cytokine cytotoxic cytotoxicity day design in vivo influenzavirus migration novel novel therapeutics pathogen receptor response therapeutic vaccine tumor

项目摘要

DESCRIPTION (provided by applicant): Recently it has become apparent that innate immunity can regulate aspects of the adaptive immune response. The aim of this proposal is to determine how dendritic cells (DC), cells of innate immunity, regulate cytotoxic CD8+ T cell responses to pathogens. To date much has been elucidated in terms of the role DC play during the initiation phase of adaptive immune responses. In particular these very potent antigen-presenting cells are critical for the initiation of antiviral CD8+ T cells responses. Mature DC expressing appropriate co-stimulation molecules are required to present antigen in order to initiate the activation of naive CD8+ T cells. What is not known, however, is whether DC play a role in the later expansion and contraction phases of the CD8+ T cell response. We have preliminary data showing that a great influx of DC occurs in the lungs of influenza type A virus infected animals 2-5 days postinfection and that costimulation is required during the later phases of the virus-specific CD8+ T cell response. By using DTR-CD11c transgenic animals we plan to deplete DC during different phases of the CD8+ T cell response and thus start to understand what role DC are playing during the later phases of CD8+ T cell response. The requirement of costimulation molecules such as CD28 or CD27 will also be investigated to delineate the mechanism of action of DC at these later stages of the response. Finally, the role of DC and whether costimulation is required in secondary CD8+ T cell responses is largely unknown. To date the classical costimulation pathway through CD28 has been extensively studied during the initiation phase of the immune response and found to be required for the maximal anti-viral CD8+ T cell response to take place. Its involvement in secondary responses is however not known even though some memory CD8+ T cells are known to express CD28. We will investigate the role of DC and the contribution of CD28 and CD27 in the secondary response and the generation of memory. In order to understand what the role of these DC is, we will investigate what are the characteristics of these pulmonary DC, whether they are infected, whether they present antigen and what cytokines they make. Finally, the mechanism that controls the migration of DC into the lungs will be investigated. The studies proposed here are novel as no previous study has examined how DC regulate expansion, contraction and the generation of memory during the later phases of the cytotoxic CD8+ T cell response. Elucidating the DC and costimulation requirements of cytotoxic CD8+ T cell responses may ultimately lead to the development of novel therapeutic and vaccine strategies against tumors and viral infections.

描述（由申请人提供）：近年来，先天免疫可以调节适应性免疫反应的各个方面已经变得很明显。本提案的目的是确定树突状细胞（DC），先天免疫细胞，如何调节细胞毒性CD8+ T细胞对病原体的反应。迄今为止，关于DC在适应性免疫应答起始阶段的作用已经有了很多阐明。特别是这些非常有效的抗原呈递细胞对于启动抗病毒CD8+ T细胞反应至关重要。表达适当共刺激分子的成熟DC需要呈递抗原，以启动初始CD8+ T细胞的激活。然而，尚不清楚DC是否在CD8+ T细胞反应的后期扩张和收缩阶段发挥作用。我们的初步数据显示，甲型流感病毒感染动物的肺部在感染后2-5天内会出现大量DC，并且在病毒特异性CD8+ T细胞应答的后期阶段需要共刺激。通过使用DTR-CD11c转基因动物，我们计划在CD8+ T细胞应答的不同阶段消耗DC，从而开始了解DC在CD8+ T细胞应答的后期阶段发挥的作用。还将研究对CD28或CD27等共刺激分子的需求，以描述DC在这些反应后期的作用机制。最后，DC的作用以及在继发性CD8+ T细胞反应中是否需要共刺激在很大程度上是未知的。迄今为止，通过CD28的经典共刺激途径已经在免疫应答的起始阶段进行了广泛的研究，并发现它是发生最大的抗病毒CD8+ T细胞应答所必需的。然而，尽管已知一些记忆性CD8+ T细胞表达CD28，但它在继发性反应中的作用尚不清楚。我们将研究DC的作用以及CD28和CD27在二次应答和记忆产生中的作用。为了了解这些DC的作用，我们将研究这些肺DC的特征，它们是否被感染，它们是否呈现抗原以及它们产生什么细胞因子。最后，将研究控制DC向肺部迁移的机制。本文提出的研究是新颖的，因为之前没有研究研究DC如何调节细胞毒性CD8+ T细胞反应后期的扩张、收缩和记忆的产生。阐明细胞毒性CD8+ T细胞反应的DC和共刺激需求可能最终导致针对肿瘤和病毒感染的新型治疗和疫苗策略的发展。