Natural killer cell and T-cell crosstalk in CMV infection

CMV 感染中的自然杀伤细胞和 T 细胞串扰

• 批准号: 9398188
• 负责人: KATHARINE C HSU
• 金额: $ 30.63万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9398188
• 关键词: Activated Natural Killer Cell; Adoptive Transfer; Affect; Alpha Cell; Antigen-Presenting Cells; Antigens; Autologous; Binding; Biological Assay; Blood specimen; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; Cell Communication; Cell Transplants; Cell physiology; Cell surface; Cells; Chronic; Cytomegalovirus; Cytomegalovirus Infections; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Equilibrium; Goals; Hematopoietic; Human; Immune; Immune response; Immune system; Immunocompromised Host; In Vitro; Incubated; Individual; Infection; Innate Immune System; Kinetics; Knowledge; Lymphocyte; Maintenance; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Natural Killer Cells; Newborn Infant; Organ; PDCD1LG1 gene; Patients; Peptides; Phenotype; Physiologic pulse; Population; Recovery; Shapes; Solid; Stem cell transplant; Surface; System; T cell response; T-Cell Proliferation; T-Lymphocyte; Transplant Recipients; Transplantation; Up-Regulation; Viral; Virus; Virus Diseases; cohort; comparative; hematopoietic cell transplantation; in vivo; inhibiting antibody; insight; mortality; mouse model; novel; pathogen; peripheral blood; prevent; reconstitution; response; seropositive

ABSTRACT Human cytomegalovirus (HCMV) is the most common cause of congenital viral infection and an important cause of morbidity and mortality following solid organ and hematopoietic cell transplantation. Understanding how the immune system responds to HCMV is vital to the efforts to achieve efficient eradication of infection. This proposal aims to identify novel relationships between NK cells and T cells during HCMV infection, with the central hypothesis that a strong T cell response to HCMV infection can abrogate the emergence of an NK memory phenotype; reciprocally, a HCMV-activated NK cell can regulate the magnitude of the T-cell response. Using a unique fully autologous in vitro HCMV infection system, regulatory relationships between NK cells and T cells can be investigated and identified. Preliminary studies have generated the novel finding that direct interaction of NK cells with HCMV-infected dendritic cells induces PD-L1 surface expression on NK cells, which directly inhibits antibody-mediated T cell proliferation. To determine the impact of PDL1+ NK cell on HCMV antigen specific T cells, T cell responses to HCMV infection will be stimulated by the use of an artificial antigen-presenting cell pulsed with CMVpp65 peptides. Co-incubation of CMV-activated PDL1+ NK cells and CMV- sensitized T cells will permit elucidation of regulatory effects of one lymphocyte on the other. Additionally, preliminary data from an in vivo murine model has recapitulated findings in the human studies, showing a significant increase in the number of PDL1+ NK cells following MCMV infection of C57BL/6 mice. Using genetically novel murine systems, the in vivo impact of PDL1+ NK cells on MCMV-specific T cell responses and the efficiency of viral clearance will be determined. These murine models will allow for correlation of strength of the NK cell response with CMV-specific T cell responses and will also provide insight to how this relationship is controlled. The understanding of NK and T cell relationships developed in the in vitro and in vivo studies will be applied to the study of expansion and maintenance of adaptive NKG2C+ NK cells in healthy human donors as well as in patients with CMV reactivation following stem cell transplantation. The availability of blood samples from a cohort of hematopoietic cell transplant patients with CMV reactivation provides the unique opportunity to examine the NK and T cell repertoire in the setting of CMV infection. These studies will describe novel mechanisms that will expand existing knowledge on the balance of the adaptive and innate immune systems during viral infection and will provide further insight to mechanisms that can be targeted to prevent reactivation and chronic viral infection.

抽象的 人类巨细胞病毒（HCMV）是先天性病毒感染的最常见原因，也是一种 实体器官和造血细胞发病和死亡的重要原因 移植。了解免疫系统如何响应 HCMV 对于这项工作至关重要 以达到高效消灭感染的目的。该提案旨在识别新的关系 HCMV 感染期间 NK 细胞和 T 细胞之间的关系，其中心假设是强 T 细胞 细胞对 HCMV 感染的反应可以消除 NK 记忆表型的出现； 相反，HCMV 激活的 NK 细胞可以调节 T 细胞反应的强度。 采用独特的全自体体外HCMV感染系统，调节关系 可以研究和鉴定 NK 细胞和 T 细胞之间的关系。初步研究有 产生了新的发现，即 NK 细胞与 HCMV 感染的树突状细胞直接相互作用 诱导 NK 细胞表面 PD-L1 表达，直接抑制抗体介导的 T 细胞 增殖。确定PDL1+ NK细胞对HCMV抗原特异性T细胞、T细胞的影响 使用人工抗原呈递细胞将刺激对 HCMV 感染的反应 用 CMVpp65 肽进行脉冲。 CMV 激活的 PDL1+ NK 细胞和 CMV- 共孵育 致敏 T 细胞将有助于阐明一种淋巴细胞对另一种淋巴细胞的调节作用。 此外，来自体内小鼠模型的初步数据概括了以下发现： 人体研究显示，PDL1+ NK 细胞的数量显着增加 C57BL/6 小鼠的 MCMV 感染。使用基因新颖的小鼠系统，体内影响 PDL1+ NK 细胞对 MCMV 特异性 T 细胞的反应和病毒清除的效率将 决定。这些小鼠模型将能够关联 NK 细胞反应的强度 与 CMV 特异性 T 细胞反应有关，也将提供关于这种关系如何发生的见解 受控。对 NK 和 T 细胞关系的理解是在体外和体内发展起来的 体内研究将应用于适应性NKG2C+ NK的扩增和维持研究 健康人类捐献者以及干细胞后巨细胞病毒再激活患者的细胞 移植。来自造血细胞移植队列的血液样本的可用性 CMV 再激活的患者提供了检查 NK 和 T 细胞的独特机会 CMV 感染情况下的曲目。这些研究将描述新的机制， 扩展关于适应性和先天免疫系统平衡的现有知识 病毒感染，并将进一步深入了解可预防的机制 再激活和慢性病毒感染。