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

巨细胞病毒（CMV）感染美国人口的一半，建立终身持续感染。1%的婴儿出生时感染CMV，其中一部分婴儿患有永久性发育障碍。CMV对免疫系统受损的个体（包括实体器官和干细胞移植患者）具有生命威胁。此外，CMV感染或再活化导致实体器官移植患者的病毒血症与慢性移植物排斥相关。通过持续的监测，自然杀伤细胞（NK）和T细胞在个体的一生中合作控制CMV。我们最近发现了一个NK细胞和T细胞亚群，携带活化CD 94-NKG 2C受体，优先响应急性CMV感染的实体器官移植受者和造血干细胞移植受者。这些CD 94-NKG 2C + NK细胞对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EB病毒的急性感染没有反应，并且仅在已感染CMV的个体中观察到这些NK细胞被重新激活。在这种CMV特异性CD 94-NKG 2C + NK细胞群中，我们已经鉴定出一种独特的NK细胞亚群，其不表达Fc“CD 94“RI“epidermal”信号转导亚基，该亚基在人体所有初始NK细胞上表达，并且这些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一个特定的人类NK细胞亚群和表达NK受体的T细胞如何对实体器官移植受者中的CMV感染或再活化作出反应，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保护免受急性CMV感染或影响移植物存活。我们将使用最先进的CyTOF质谱分析和功能测定来评估控制或未能控制CMV感染或再激活的肾移植患者中NK细胞应答的动力学。项目2中的这些研究将补充项目1中的T细胞和项目3中的B细胞研究，以确定针对CMV的先天性和适应性免疫应答之间的动态相互作用和交叉调节。

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.