Innate immune control of the oncogenic Epstein Barr virus by natural killer (NK) cells

高度免疫缺陷小鼠模型的出现，在移植造血祖细胞后重建人类免疫系统成分，为解决体内人类免疫系统生物学的基本问题和转化问题提供了独特的机会。Christian m<e:1> nz领导的客座实验室成功建立了人CD34+造血祖细胞植入NSG小鼠，并连续发育出功能性的人多系免疫细胞。利用这一策略，m<s:1> nz和同事可以证明重建的NSG小鼠模型再现了人类致癌eb病毒（EBV）原发感染的关键方面，以及EBV相关肿瘤和t细胞介导的免疫控制。此外，我们最近在重组NSG小鼠中描述了人类自然杀伤（NK）细胞区室，并可以证明这些先天淋巴细胞的功能能力。由于大量的研究已经确定了NK细胞在小鼠的免疫反应中对感染和癌症的保护作用，但在人类中缺乏这种作用的结论性证据，我们现在想解决人类NK细胞在体内控制EBV感染和监测EBV诱导肿瘤中的作用。在这些研究中，我们将表征人NK细胞亚群在体内EBV感染期间的扩增和激活，在EBV感染期间的消耗或扩增，并研究这些操作对病毒滴度和肿瘤发展的影响，以及表征T细胞介导的免疫控制在这些治疗中的差异。我们认为这些方法将使我们能够在高度翻译的环境中为理解人类NK细胞在控制EBV感染和肿瘤监测中的作用做出重大贡献。这些研究获得的结果可能会拓宽我们对NK细胞在对抗病毒感染和癌症方面的潜在免疫治疗选择的认识。

The advent of highly immunodeficient mouse models that reconstitute human immune system components after transfer of hematopoietic progenitor cells opens the unique opportunity to address basic as well as translational questions to the biology of the human immune system in vivo. The guest lab headed by Christian Münz was able to establish engraftment of NSG mice with human CD34+ hematopoietic progenitor cells and consecutive development of functional human multi-lineage immune cells. Using this strategy Münz and colleagues could show that the reconstituted NSG mouse model reproduces key aspects of primary infection by the human oncogenic Epstein Barr virus (EBV) as well as EBV-associated tumors and T-cell mediated immune control thereof. Furthermore, we recently described the human natural killer (NK) cell compartment in reconstituted NSG mice and could demonstrate the functional competence of these innate lymphocytes. Since numerous studies have established the protective role of NK cells in the immune response against infections and cancer in mice, but conclusive evidence of this effect is lacking in humans, we now would like to address the role of human NK cells in vivo in the control of EBV infection and surveillance of EBV-induced tumors. For these studies we will characterize expansion and activation of human NK cell subsets during EBV infection in vivo, deplete or expand them during EBV infection and investigate the effects of these manipulations on viral titer and tumor development as well as characterize differences in T cell-mediated immune control upon these treatments. We think these approaches will allow us in a highly translational setting to contribute substantially to the understanding of the role of human NK cells in the control of EBV infection and tumor surveillance. The results obtained by these studies will likely broaden our insight into potential immunotherapeutic options of NK cells in the fight against viral infection and cancer.