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%的婴儿出生时感染巨细胞病毒，其中一部分婴儿患有永久性发育障碍。巨细胞病毒对免疫系统受损的个体，包括实体器官和干细胞移植患者，是危及生命的。此外，实体器官移植患者感染或再激活巨细胞病毒导致病毒血症与慢性移植排斥反应相关。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共同控制巨细胞病毒。我们最近发现NK细胞和T细胞亚群携带活化CD94-NKG2C受体，在实体器官移植受者和造血干细胞移植受者中优先响应急性巨细胞病毒感染。这些CD94-NKG2C+ NK细胞对巨细胞病毒是特异性的，因为它们在感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，并且这些NK细胞仅在感染巨细胞病毒的个体中被观察到重新激活。在这个cmv特异性CD94-NKG2C+ NK细胞群中，我们发现了一个独特的NK细胞亚群，它不表达Fc“epsilon”RI“epsilon”信号亚基，它在人类所有naïve 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人类NK细胞和表达NK受体的T细胞的特定亚群如何对实体器官移植受者的巨细胞病毒感染或再激活做出反应，以及这些细胞的频率或它们对感染的动力学反应是否有助于宿主抵抗急性巨细胞病毒感染或影响移植物存活。我们将使用最先进的CyTOF质量细胞术和功能分析来评估肾移植患者控制或无法控制CMV感染或再激活的NK细胞反应动力学。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细胞的研究，以确定先天性和适应性免疫应答对巨细胞病毒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.