Functional analysis of NK cells and their potential to generate CTL responses

NK 细胞的功能分析及其产生 CTL 反应的潜力

• 批准号: 8091360
• 负责人: KASPER HOEBE
• 金额: $ 36.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091360
• 关键词: Allografting; Antigen Presentation; Antigens; Apoptosis; Apoptotic; Autoimmunity; Automobile Driving; B-Cell Activation; B-Lymphocytes; Bacterial Infections; Biological; CD4 Positive T Lymphocytes; CD8B1 gene; CD95 Antigens; Cell Death; Cell physiology; Cells; Cessation of life; Data; Dendritic Cells; Development; Disease; Exhibits; Generations; Goals; Granzyme; Humoral Immunities; Immune; Immune response; Immune system; Immunization; In Vitro; Infection; Interferons; Interleukin-1; Interleukin-12; Interleukin-18; Laboratories; Ligation; Lymphoid; Mediating; Molecular; NK Cell Activation; Natural Killer Cells; Neoplasms; Pathway interactions; Production; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Stimulus; Surface; T cell response; T-Lymphocyte; Tissues; Tumor Necrosis Factor Ligand Superfamily Member 6; Vaccination; Vaccines; Viral; Work; design; immune activation; immunogenicity; in vivo; insight; killings; long term memory; neoplastic; neoplastic cell; novel; novel strategies; pathogen; perforin; programs; public health relevance; response; vaccine development

DESCRIPTION (provided by applicant): Functional analysis of NK cells and their potential to generate CTL responses Natural Killer (NK) cells detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. However, recent work in our laboratory suggests that they discharge another duty as well: one that establishes a strong tie between NK cells and their relatives in the adaptive immune system. By inducing apoptosis of cells that exhibit "missing self", NK cells prompt a strong CD8+ T, CD4+ T and B cell response. The adaptive immune responses via this pathway are significantly amplified compared to immune responses observed after immunization with 3-irradiated cells. While in previous studies, we found that the adaptive immune responses induced by 3-irradiated cells occurred independent of MyD88/Trif signaling, the responses induced by NK cell- mediated cell death-particularly the amplification observed in this pathway-requires a MyD88/Trif-dependent component. Further studies in vitro, have revealed that lymphoid DCs release increased levels of IL-12 when exposed to cells rendered apoptotic by Fas- ligation (but not when exposed to 3-irradiated cells), suggesting that IL-12 production and subsequent MyD88 pathway signaling could be responsible for the amplification observed in this pathway. In the current proposal, we aim to understand the underlying molecular mechanisms and biological consequences of: (a) the contributions of NK cell- specific pathways to the generation of robust CD8+ T cell responses; (b) the DC-specific activation pathways induced by (NK cell-mediated) cell death that drive CD8+ T cell responses. Finally (c), we aim to understand the underlying molecular mechanisms and biological consequences of CD4+ T and B cell responses driven by this pathway. Ultimately, this newly identified function of NK cells may have important implications for a wide variety of diseases, and may be exploited in the design of effective vaccines that promote strong cell-mediated and humoral immunity. PUBLIC HEALTH RELEVANCE: We believe that the NK->DC->T/B cell axis represents a fundamental pathway for the generation of robust adaptive immune responses that may provide a unique and powerful strategy for vaccine development. In addition, a better understanding of this pathway may be essential to provide insight into the development and/or control of a wide variety of diseases, including viral/bacterial infections, autoimmunity, and/or neoplastic diseases.

描述（由申请人提供）：NK细胞的功能分析及其产生CTL反应的潜力自然杀伤（NK）细胞检测并杀死病原体感染的宿主细胞，以及肿瘤细胞和同种异体组织移植物。然而，我们实验室最近的工作表明，它们还履行了另一项职责：在NK细胞和它们在适应性免疫系统中的亲属之间建立了牢固的联系。NK细胞通过诱导出现“自我缺失”的细胞凋亡，引发强烈的CD8+ T、CD4+ T和B细胞应答。与3辐照细胞免疫后观察到的免疫应答相比，通过该途径的适应性免疫应答显着扩增。虽然在之前的研究中，我们发现3-辐照细胞诱导的适应性免疫反应独立于MyD88/Trif信号发生，但NK细胞介导的细胞死亡诱导的反应-特别是在该途径中观察到的扩增-需要MyD88/Trif依赖性成分。进一步的体外研究表明，当暴露于Fas-结扎导致凋亡的细胞时，淋巴样dc释放的IL-12水平增加（但暴露于3-辐照细胞时则没有），这表明IL-12的产生和随后的MyD88通路信号传导可能是该途径中观察到的扩增的原因。在目前的提案中，我们的目标是了解潜在的分子机制和生物学后果：(a) NK细胞特异性途径对产生强大的CD8+ T细胞反应的贡献；(b)由NK细胞介导的细胞死亡诱导的dc特异性激活途径，驱动CD8+ T细胞反应。最后(c)，我们的目标是了解由该途径驱动的CD4+ T和B细胞反应的潜在分子机制和生物学后果。最终，这种新发现的NK细胞功能可能对多种疾病具有重要意义，并可能在设计有效的疫苗中被利用，以促进强大的细胞介导和体液免疫。