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全球重大的健康问题。 CD8+ T细胞无法消除感染，例如HIV和HCV，它们具有病理后果。由于几种抑制机制，针对这些病毒的T细胞被无效。尽管T细胞在控制这些病毒感染中显然重要，但最近的数据表明，天然杀伤（NK）细胞也有助于控制病毒或发病机理。调节NK细胞受体的基因内的遗传多态性与HCV分辨率有关。我们使用已建立的T细胞衰竭的小鼠模型，该模型准确地反映了人类T细胞在持续感染后如何进行功能失活。我们发现了一种有助于T细胞耗尽的新机制。 NK细胞在小鼠中征服了小鼠中的病毒特异性CD8+ T细胞反应，这些小鼠有淋巴细胞脉络膜脑膜炎病毒（LCMV）的菌株，该病毒（LCMV）广泛传播并建立了持久性。消除感染小鼠的NK细胞可改善病毒特异性的T细胞功能和数量，并大大加速病毒清除率。我们希望更好地理解NK细胞在持续存在病毒感染的背景下如何抑制T细胞反应，并了解NK细胞的更广泛的免疫调节功能。我们的初步数据表明，来自NK缺乏的小鼠的抗原呈递细胞（APC）优于NK细胞重复小鼠的APC。我们的中心假设是，在传播病毒感染期间，干扰素水平升高激活NK细胞以抑制或耗尽APC，从而导致T细胞耗尽并有限地控制病毒。 AIM1的目标是确定NK细胞的抑制T细胞反应是否受到暴露于急性或持续存在LCMV感染的小鼠中的干扰素信号传导的控制。将野生型NK细胞的体内活性与干扰素受体不足的细胞进行比较。 AIM2的目标是检查NK细胞是否消除APC或表达抑制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。这些努力将支持一项长期努力，以探讨感染天生的感应与T细胞命运确定之间的联系。这些目标与改善疫苗和治疗剂的设计有关，以防止细胞耗尽并维持保护性免疫呼吸，这是NIH，NIAID的指定任务。该项目收集的信息可能会使感染免疫学超越肿瘤免疫学，在这种情况下，T细胞耗尽是成功的T细胞免疫疗法的重大障碍。