Enhancing Pathogen-specific Memory CD8+ T cell Responses in Vivo

增强体内病原体特异性记忆 CD8 T 细胞反应

基本信息

批准号：
8960918
负责人：
Gregoire Stephane Lauvau
金额：
$ 41.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-15 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960918
关键词：
Achievement Affect Animals Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmunity Autophagocytosis Bacteria CCL3 gene CD8B1 gene Categories Cells Chronic Cytokine Receptors Data Dendritic Cells Development Disease Effector Cell Event Foundations Future Genetic Goals Growth Health Histocompatibility Antigens Class I Hour Human Immune Immune response Immune system Immunity Immunotherapy In Situ Inbred NOD Mice Infection Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Interferon Type I Interferons Interleukin-15 Interleukin-18 Lead Leishmania Life Listeria monocytogenes Longevity Lymphocyte Maintenance Measures Mediating Memory Methods Modeling Molecular Murid herpesvirus 1 Mus Myelogenous Outcome Pancreas Pathogenesis Pathway interactions Phagocytes Play Process Production Reactive Oxygen Species Research Role Signal Transduction Site Source System T cell differentiation T cell response T memory cell T-Cell Activation T-Lymphocyte Testing Time Tissues Vaccination Vaccines Work antimicrobial arm chemokine chronic autoimmune disease cytokine cytotoxic design fighting improved in vivo innovation killings microbial monocyte mouse model neutrophil novel therapeutics pathogen response success tumor vaccination strategy vaccine-induced immunity

项目摘要

DESCRIPTION (provided by applicant): The design of better vaccines focuses on optimizing numbers, functional features and longevity of memory cells in vivo. Current research indicates that the achievement of such goals involves optimizing three distinct signals during vaccination, which are antigen presentation, co-stimulation and inflammation. The effective delivery of these signals during the priming of vaccine-induced immunity is usually associated with robust effector and memory lymphocyte responses, and the ability of memory T cells to efficiently re-expand upon secondary antigen encounter. In addition, maintenance of memory cells is dependent on homeostatic cytokines and expression of sufficient levels of the receptors for these cytokines. While unraveling the mechanisms of differentiation of T cells into potent memory cells is critical to improve vaccination strategies, an alternative possibility that has only been minimally explored is to develop methods to enhance the activation and expression of effector functions of vaccine-induced memory T cells at the time of infection. The success of such an approach requires a thorough understanding of how memory T cells undergo activation in vivo, which is a major goal of the current proposal. Over the past several years, we developed an experimental system to study the activation of memory CD8+ T cells in vivo in mice infected with the intracellular bacterium Listeria monocytogenes (Lm). With this system, we established that memory CD8+ T cells with the capacity to protect against lethal infection secreted the proinflammatory chemokine CCL3/MIP1 upon recognition of their cognate antigen, a feature that was lacking in memory cells from non-protected animals. CCL3 secretion by protective memory CD8+ T cells promoted efficient recruitment and activation of phagocytes, specifically neutrophils and a distinct subset of monocytes known as "inflammatory monocytes", leading to microbial pathogens elimination. Most interestingly, our recent data show that the initial activation of memory CD8+ T cells in vivo is orchestrated by inflammatory monocytes and is independent of recognition of cognate antigen. Our working hypothesis postulates that inflammatory monocytes are central to optimal recall immune responses, both through activation of memory cells and for effective clearance of microbial pathogens. The current application proposes to investigate the molecular mechanisms that regulate memory CD8+ T cell activation in vivo and lead to enhanced pathogen killing. We will also assess such mechanism in models of inflammatory diseases such as type I diabetes. As specific aims for this proposal, we will establish (i) the contribution of cognate antigen recognition and inflammatory signals to memory CD8+ T cell activation in vivo, (ii) how inflammatory monocytes orchestrate the reactivation of memory CD8+ T cells and (iii) whether inflammatory monocytes contribute to memory CD8+ T cell-mediated autoimmunity. We anticipate the results of this work to lay the foundations for best design of future therapies modulating the reactivation of memory CD8+ T cells.

描述（由申请人提供）：更好的疫苗的设计着重于优化体内存储单元的数字，功能特征和寿命。当前的研究表明，此类目标的实现涉及在疫苗接种过程中优化三个不同的信号，即抗原表现，共刺激和炎症。在疫苗诱导的免疫力启动过程中，这些信号的有效传递通常与稳健的效应子和记忆淋巴细胞反应有关，以及记忆T细胞在二次抗原遇到时有效重新扩张的能力。此外，记忆细胞的维持取决于稳态细胞因子和这些细胞因子的足够水平的受体表达。虽然将T细胞分化为有效记忆细胞的机制对于改善疫苗接种策略至关重要，但仅探索的替代可能性是开发方法来增强疫苗诱导的记忆T细胞在感染时的激活和表达。这种方法的成功需要透彻了解记忆T细胞如何在体内进行激活，这是当前建议的主要目标。在过去的几年中，我们开发了一个实验系统，研究了感染细胞内细菌单核细胞增生菌（LM）的小鼠体内记忆CD8+ T细胞的激活。使用该系统，我们确定了具有预防致命感染的能力的记忆CD8+ T细胞在识别其同源抗原后，将促炎性趋化因子CCL3/MIP1分泌出来，这一特征缺乏非保护动物的记忆细胞。保护性记忆CD8+ T细胞的CCL3分泌促进了吞噬细胞的有效募集和激活，特别是中性粒细胞和一个被称为“炎症单核细胞”的独特子集，导致消除微生物病原体。最有趣的是，我们最近的数据表明，体内记忆CD8+ T细胞的初始激活是由炎症单核细胞精心策划的，并且独立于识别同源抗原。我们的工作假设假设炎症单核细胞是通过激活记忆细胞和有效清除微生物病原体的最佳回忆免疫反应的核心。当前的应用建议研究调节体内记忆CD8+ T细胞活化并导致病原体杀伤增强的分子机制。我们还将在炎症性疾病（例如I型糖尿病）的模型中评估这种机制。作为该提议的具体目的，我们将建立（i）抗原识别和炎症信号对体内内存CD8+ T细胞激活的贡献，（ii）炎症单核细胞如何调节记忆CD8+ T细胞和（iii）炎症单细胞是否有助于存储单细胞的内存CD8+ T细胞+ T细胞+ T Cell+ T细胞介导。我们预计这项工作的结果是为未来疗法的最佳设计奠定基础，以调节记忆CD8+ T细胞的重新激活。