Project 2: Natural Killer Cell Response to Cytomegalovirus Infection in Renal Transplantation

项目2：肾移植中自然杀伤细胞对巨细胞病毒感染的反应

• 批准号: 10000882
• 负责人: LEWIS Lee LANIER
• 金额: $ 25.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000882
• 关键词: Acute; Address; Antibody-Dependent Enhancement; Antiviral Agents; B-Lymphocytes; Biological Assay; Cells; Chronic; Clinical; Complement; Cytomegalovirus; Cytomegalovirus Infections; Cytometry; Cytotoxic T-Lymphocytes; Developmental Disabilities; Disease; Fc epsilon RI; Frequencies; Goals; Graft Rejection; Graft Survival; Hematopoietic Stem Cell Transplantation; Herpesviridae; Host Defense; Human; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Individual; Infant; Infection; Infection Control; Infectious Mononucleosis; Inflammation; KLRD1 gene; Kidney Transplantation; Kinetics; Life; Morbidity - disease rate; Natural Killer Cells; Organ; Organ Transplantation; Patients; Persons; Population; Primary Infection; Prophylactic treatment; Receptor Cell; Regulation; Role; Severities; Signal Transduction; Simplexvirus; Solid; Stem cell transplant; Systems Biology; T-Lymphocyte; Technology; Transplant Recipients; Transplantation; Viral; Viremia; acute infection; adaptive immune response; antibody-dependent cell cytotoxicity; chronic infection; insight; mortality; novel; novel strategies; receptor; response; senescence

Cytomegalovirus (CMV) infects half of the US population, establishing a lifetime persistent infection. One percent of infants are born with CMV infection and a subset of these infants suffers permanent developmental disabilities. CMV is life-threatening for individuals with a compromised immune system, including solid organ and stem cell transplant patients. Additionally, infection or reactivation of CMV resulting in viremia in solid organ transplant patients has been correlated with chronic graft rejection. Through constant surveillance, natural killer (NK) and T cells cooperatively control CMV throughout an individual’s life. We have recently identified a subpopulation of NK cells and T cells bearing the activating CD94-NKG2C receptor that preferentially respond to acute CMV infection in both solid organ transplant recipients and hematopoietic stem cell transplantation recipients. These CD94-NKG2C+ NK cells are specific for CMV, in that they do not respond to acute infection with Epstein-Barr virus during infectious mononucleosis or Herpes Simplex Virus, and these NK cells have only been observed to be re-activated in individuals who have been infected with CMV. Within this CMV-specific CD94-NKG2C+ NK cell population we have identified a unique subset of NK cells that do not express the Fc"epsilon"RI"episilon" signaling subunit, which is expressed on all naïve NK cells in humans, and these NK cells possess enhanced antibody-dependent cellular cytotoxicity function. The overall goal of this project is to determine how a specific subset of human NK cells and T cells expressing NK receptors respond to CMV infection or reactivation in solid organ transplant recipients and whether the frequency of these cells or their kinetic response to infection contributes to host protection against acute CMV infection or influences graft survival. We will use state-of-the-art CyTOF mass cytometry and functional assays to evaluate the kinetics of the NK cell response in kidney transplant patients who control or fail to control infection or reactivation of CMV. These studies in Project 2 will complement studies of T cells in Project 1 and B cells in Project 3 to define the dynamic interactions and cross-regulation between the innate and adaptive immune response against CMV.

巨细胞病毒 (CMV) 感染了一半的美国人口，造成终生持续感染，百分之一的婴儿出生时就患有巨细胞病毒感染，其中一部分婴儿患有巨细胞病毒，对于免疫系统受损的人来说会危及生命。此外，通过持续监测，自然杀伤细胞 (NK) 和 T 细胞在整个过程中协同控制 CMV，导致实体器官移植患者出现病毒血症。我们最近发现了一个带有激活性 CD94-NKG2C 受体的 NK 细胞和 T 细胞亚群，它们优先响应实体器官移植受者和造血干细胞移植受者中的急性 CMV 感染。对 CMV 具有特异性，因为它们在传染性单核细胞增多症或单纯疱疹病毒期间对 Epstein-Barr 病毒的急性感染没有反应，并且这些仅观察到NK细胞在已感染CMV的个体中重新激活，在该CMV特异性CD94-NKG2C+NK细胞群中，我们鉴定了不表达Fc“ε”RI的独特NK细胞子集。 “episilon”信号亚基在人类所有天然 NK 细胞上表达，这些 NK 细胞具有增强的抗体依赖性细胞毒性功能，该项目的总体目标是确定特定亚群如何发挥作用。我们将使用人类 NK 细胞和表达 NK 受体的 T 细胞对实体器官移植受者中 CMV 感染或重新激活的反应，以及这些细胞的频率或其对感染的动力学反应是否有助于宿主免受急性 CMV 感染或影响移植物存活。最先进的 CyTOF 质谱流式细胞术和功能测定，用于评估控制或未能控制 CMV 感染或再激活的肾移植患者的 NK 细胞反应动力学。项目 2 中的这些研究将补充以下研究。项目 1 中的 T 细胞和项目 3 中的 B 细胞定义了针对 CMV 的先天免疫反应和适应性免疫反应之间的动态相互作用和交叉调节。