NK cell regulation of adaptive immunity during persisting virus infection

持续病毒感染期间 NK 细胞对适应性免疫的调节

• 批准号: 8891633
• 负责人: JASON Kyle WHITMIRE
• 金额: $ 38万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891633
• 关键词: Activated Natural Killer Cell; Acute; Antigen Presentation; Antigen-Presenting Cells; Antiviral Agents; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell division; Cell physiology; Cells; Chronic; Data; Dendritic Cells; Disease; Endothelial Cells; Genes; Genetic Polymorphism; Glean; Goals; Granzyme; HIV; Health; Hepatitis C virus; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunobiology; Immunology; Immunotherapy; Infection; Inflammation; Interferons; Interleukin-10; Lead; Link; Lymphocytic choriomeningitis virus; Mediating; Memory; Mission; Mus; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Pathogenesis; Population; Production; Recruitment Activity; Regulation; Resolution; Role; Signal Transduction; T cell response; T memory cell; T-Lymphocyte; Testing; Translating; United States National Institutes of Health; Vaccine Design; Viral; Virus; Virus Diseases; Wing; adaptive immunity; cell killing; cytokine; exhaust; exhaustion; improved; in vivo; macrophage; memory recall; mouse model; prevent; receptor; response; therapeutic vaccine; tumor immunology

DESCRIPTION (provided by applicant): Diseases caused by chronic virus infections are a significant worldwide health problem. CD8+ T cells fail to eliminate infections, such as HIV and HCV, which establish persistence with pathological consequences. T cells specific for these viruses are rendered ineffectual due to several suppression mechanisms. Despite the clear importance of T cells in the control of these virus infections, recent data indicate that natural killer (NK) cells also contribute to virus control or pathogenesis. Genetic polymorphisms within genes that regulate NK cell receptors are associated with HCV resolution. We use an established mouse model of T cell exhaustion that accurately reflects how human T cells undergo functional inactivation following persisting infection. We found a new mechanism that contributes to T cell exhaustion. NK cells subdue virus-specific CD8+ T cell responses in mice that are given a strain of lymphocytic choriomeningitis virus (LCMV) that disseminates widely and establishes persistence. Eliminating NK cells in infected mice improves virus-specific T cell function and number and vastly expedites viral clearance. We wish to better understand how NK cells restrain T cell responses in the context of persisting virus infection and understand the wider immunoregulatory functions of NK cells. Our preliminary data show that antigen presenting cells (APC) from NK-depleted mice are superior to APCs from NK cell-replete mice. Our central hypothesis is that during disseminating virus infection, elevated levels of interferon activate NK cells to inhibit or deplete APCs, which leads to T cell exhaustion and limited virus control. The objectives of Aim1 are to determine whether NK cell inhibition of T cell responses is governed by interferon signaling in mice that are exposed to acute or persisting LCMV infection. The in vivo activity of wildtype NK cells will be compared to those that are deficient in interfero-receptors. The objectives of Aim2 are to examine whether NK cells eliminate APCs or express suppressive cytokines that impair T cells or the stimulatory functions of APCs. The objectives of Aim3 are to determine whether NK cells inhibit memory T cell and B cell responses. The objectives of Aim4 are to explore whether memory NK cells persist to influence long-term immune responses. Overall, this project concerns the basic immunobiology of persisting virus infections. These efforts will support a long-term endeavor to explore the links between innate sensing of infection and T cell fate determination. These goals are relevant to improving the design of vaccines and therapeutics to prevent T cell exhaustion and sustain protective immune respones, which is a stated mission of the NIH, NIAID. Information gleaned from this project may translate beyond infection immunology to tumor immunology, where T cell exhaustion is a significant hurdle to successful T cell immunotherapies.

描述（由申请人提供）：由慢性病毒感染引起的疾病是一个重大的世界性健康问题。 CD8+ T 细胞无法消除 HIV 和 HCV 等感染，这些感染会持续存在并产生病理后果。由于多种抑制机制，针对这些病毒的特异性 T 细胞变得无效。尽管 T 细胞在控制这些病毒感染中具有明显的重要性，但最近的数据表明自然杀伤 (NK) 细胞也有助于病毒控制或发病机制。调节 NK 细胞受体的基因内的遗传多态性与 HCV 消退相关。我们使用已建立的 T 细胞耗竭小鼠模型，该模型准确反映了人类 T 细胞在持续感染后如何经历功能失活。我们发现了一种导致 T 细胞耗竭的新机制。在给予小鼠淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 毒株的小鼠中，NK 细胞可抑制病毒特异性 CD8+ T 细胞反应，该病毒株可广泛传播并建立持久性。消除受感染小鼠中的 NK 细胞可以改善病毒特异性 T 细胞的功能和数量，并大大加快病毒清除速度。我们希望更好地了解 NK 细胞在持续病毒感染的情况下如何抑制 T 细胞反应，并了解 NK 细胞更广泛的免疫调节功能。我们的初步数据表明，来自 NK 耗尽小鼠的抗原呈递细胞 (APC) 优于来自 NK 细胞充足小鼠的 APC。我们的中心假设是，在病毒感染传播过程中，干扰素水平升高会激活 NK 细胞抑制或消耗 APC，从而导致 T 细胞耗竭并限制病毒控制。 Aim1 的目的是确定暴露于急性或持续 LCMV 感染的小鼠中 NK 细胞对 T 细胞反应的抑制是否受到干扰素信号传导的控制。野生型 NK 细胞的体内活性将与那些缺乏干扰素受体的细胞进行比较。 Aim2 的目标是检查 NK 细胞是否消除 APC 或表达损害 T 细胞或 APC 刺激功能的抑制性细胞因子。 Aim3 的目标是确定 NK 细胞是否抑制记忆 T 细胞和 B 细胞反应。 Aim4 的目标是探索记忆 NK 细胞是否持续影响长期免疫反应。总体而言，该项目涉及持续病毒感染的基本免疫生物学。这些努力将支持探索先天感染感知与 T 细胞命运决定之间联系的长期努力。这些目标与改进疫苗和治疗方法的设计相关，以防止 T 细胞耗竭并维持保护性免疫反应，这是 NIH、NIAID 的既定使命。从该项目中收集的信息可能会从感染免疫学转化为肿瘤免疫学，在肿瘤免疫学中，T 细胞耗竭是 T 细胞免疫疗法成功的一个重大障碍。