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：
10471178
负责人：
Gregoire Stephane Lauvau
金额：
$ 58.31万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471178
关键词：
Abnormal Cell Antibody Response Antigen-Presenting Cells Antigens Autophagocytosis B-Lymphocytes Bacteria Binding CCL3 gene CCL4 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXCL9 gene CXCR3 gene Cells Cellular biology Chemotaxis Clonal Expansion Constitution Containment Cues Cytolysis Effector Cell Event Funding GBP1 gene Gene Expression Genes Genetic Genetic Transcription Goals Grant Growth Hour I-antigen IRF4 gene ITGAM gene Immune Immune response Immunity Immunize Immunotherapy In Vitro Individual Infection Inflammatory Interferons Interleukin-15 Interleukin-18 Invaded Laboratories Lead Leukocytes Listeria monocytogenes Lymphocyte Mediating Memory Microbe Modeling Molecular Mus Natural Killer Cells Phagocytes Play Population Process Production Protein Family Proteins Provider Public Health Reactive Oxygen Species Regulation Reporting Role Signal Transduction Site Study models T cell response T cell therapy T-Lymphocyte TNF gene Testing Therapeutic Up-Regulation Vaccinated Vaccination Vaccines Work XCL1 gene base chemokine cytokine design guanylate imaging approach immunoregulation improved in vivo intravital imaging loss of function microbial microbicide monocyte multi-photon neoplastic cell neutrophil novel novel strategies pathogen pathogenic microbe programs recruit response transcription factor tumor

项目摘要

Abstract Memory CD8+ T cells are essential adaptive effector cells of immune defenses because they are extremely efficient at sensing intracellular pathogens and tumors. The chief effector feature of CD8+ T cells is their ability to recognize and kill infected and “abnormal” cells but they also produce multiple effector cytokines and chemokines that contribute to orchestrate protective immune responses. The cellular and molecular stepwise mechanisms by which memory CD8+ T cells in vaccinated hosts are reactivated and mediate protection is not well understood. Answering to this question has the potential to lead to novel strategies to harness or redirect the power of CD8+ T cells to the benefit of the host in many therapeutic contexts. Over the years, using mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) as model, we have contributed to show that during recall infection, vaccine-induced memory CD8+ T cells quickly sense sets of inflammatory cytokines released from various antigen-presenting cells (APCs), which initiate a rapid effector program in the memory CD8+ T cells. This includes notably the secretion of the potent immunomodulatory cytokine IFN which further signals and activates microbicidal functions inside phagocytes, a necessary process for efficient protection of vaccinated hosts. Yet, IFN is secreted to similar extent whether cognate T cell antigens are present or not. Protection, however, is antigen-specific, suggesting that other factors distinct from memory CD8+ T cell-derived IFN account for IFN-mediated protection. This proposal investigates these factors and their regulation in the memory CD8+ T cells, which APCs provide cognate antigen to the memory CD8+ T cells during recall infection and the dynamic interactions of memory CD8+ T cells and killer phagocytes using cutting-edge intravital imaging approaches. Finally, we will also dissect the mechanisms of IFN-dependent cell-autonomous defenses that are triggered inside activated phagocytes. We predict successful completion of the proposed work will have a broad impact in the field of T cell biology and vaccines, and potentially important therapeutic implications.

抽象的记忆CD8+ T细胞是免疫防御的必不可少的自适应效应细胞有效地感应细胞内病原体和肿瘤。 CD8+ T细胞的主要效应子特征是它们的能力识别并杀死感染和“异常”细胞，但它们也会产生多种效应子细胞因子，并且趋化因子有助于编排受保护的免疫复杂的趋化因子。细胞和分子逐步接种宿主中的记忆CD8+ T细胞被重新激活而介导保护的机制不是理解。回答这个问题有可能导致利用或重定向的新型策略在许多治疗性情况下，CD8+ T细胞的功率对宿主的好处。多年来，使用小鼠用细胞内细菌李斯特菌单核细胞增生（LM）作为模型进行免疫，我们为表明在召回感染期间，疫苗诱导的记忆CD8+ T细胞迅速感知炎症的集合从各种抗原呈递细胞（APC）释放的细胞因子，该细胞启动了快速效应程序内存CD8+ T细胞。这特别包括有效的免疫调节细胞因子IFN的分泌进一步的信号并激活吞噬细胞内的微生物功能，这是有效的必要过程保护接种的宿主。然而，IFN分泌在类似的程度上是否存在。但是，保护特定于抗原，表明其他因素与记忆不同 CD8+ T细胞衍生的IFN解释了IFN介导的保护。该提案调查了这些因素和它们在存储器CD8+ T细胞中的调节，APC为记忆CD8+ T细胞提供同源抗原在召回感染和记忆CD8+ T细胞和杀手吞噬细胞的动态相互作用期间尖端的浸润成像方法。最后，我们还将剖析依赖IFN的机制在活化的吞噬细胞内触发的细胞自主防御。我们预测成功完成拟议的工作将对T细胞生物学和疫苗的领域产生广泛的影响，并可能重要治疗意义。