Birc5 as a regulator of NK cell development and immune function

摘要 自然杀伤（NK）细胞是介导针对病毒病原体的免疫防御的细胞毒性淋巴细胞， 肿瘤的在临床环境中，NK细胞被靶向用于过继性细胞转移（ACT）和造血干细胞移植。 细胞移植（HSCT）方案和免疫疗法，以治疗癌症和癌症相关疾病。 感染.有效的NK细胞免疫是基于在免疫系统中持续存在功能性NK细胞库。 外围。在稳定状态下，NK细胞生态位通过新NK细胞的持续发育来维持 来自骨髓中的祖细胞群体和通过骨髓中成熟NK细胞的稳态扩增， 外围此外，某些炎性信号可能会短暂扩增NK细胞， 在感染或恶性肿瘤期间的保护。了解控制这些过程的分子途径 将对临床上基于NK细胞的新型和更有效疗法的发展产生重大影响。 我们的初步研究强调了凋亡蛋白抑制剂（IAP）Birc5的关键作用， NK细胞造血和功能。先前对干细胞和癌细胞的研究表明，Birc5 有助于广泛的细胞功能，包括有丝分裂，存活和细胞代谢， 通过其分别在细胞核、细胞质和线粒体中的高度区室化的活动。一 Birc5在NK细胞生物学中的作用尚未被描述。我们实验室的新数据表明，Birc5是一种高度和 在骨髓发育过程中经历扩增的NK细胞中瞬时上调，或 周围的病毒感染此外，我们的初步研究表明，Birc5缺陷严重损害了 小鼠NK细胞发育和成熟。Birc5在NK细胞中的特异性细胞功能，以及其在NK细胞中的表达。 在体内平衡和感染相关的NK细胞扩增中的作用仍有待确定。因此，我们将进行 这些研究验证了中心假设，即Birc5在关键细胞因子和代谢生长的下游起作用。 在发育和外周免疫过程中协调NK细胞扩增的信号。这些研究将利用 一种新的转基因小鼠，其中Birc5基因可以在NK细胞中以细胞特异性或条件性的方式缺失， 以这种方式，研究Birc5对NK细胞增殖、存活和代谢功能的贡献。 发育、稳态扩张和体内抗病毒免疫应答的环境。此外，我们将 联合收割机复杂的分子和遗传技术，以确定环境线索和细胞内 在NK细胞中调节Birc5功能的信号网络。最后，我们将使用一种创新的鼠标 异种移植模型以研究体内人NK细胞中Birc5功能。最终，我们的研究有可能 为正在进行和未来的基于NK细胞的免疫疗法提供信息，包括过继性细胞转移（ACT）， 造血干细胞转移（HSCT）方案，其利用NK细胞的抗肿瘤特性来治疗 癌 !

ABSTRACT Natural Killer (NK) cells are cytotoxic lymphocytes that mediate immune defense against viral pathogens and tumors. In clincial settings, NK cells are being targeted in adoptive cell transfer (ACT) and hematopoietic stem cell transplantation (HSCT) regimens, and immunotherapeutic approaches, to treat cancer and cancer-related infections. Effective NK cell immunity is predicated on the sustained presence of a pool of functional NK cells in the periphery. At steady state, the NK cell niche is maintained by the continual development of new NK cells from progenitor populations in the bone marrow and by the homeostatic expansion of mature NK cells in the periphery. In addition, certain inflammatory signals may transiently expand effector NK cells needed for protection during infection or malignancy. Understanding the molecular pathways that control these processes will critically impact the development of novel and more effective NK cell-based therapies in the clinic. Our preliminary studies have highlighted a critical role for the Inhibitor of Apoptosis Protein (IAP), Birc5, in NK cell hematopoiesis and function. Prior studies in stem cells and cancer cells have shown that Birc5 contributes to a broad range of cellular functions, including mitosis, survival, and cellular metabolism, acting through its highly compartmentalized activities in the nucleus, cytoplasm, and mitochondria, respectively. A role for Birc5 in NK cell biology has not been described. New data in our lab indicate that Birc5 is highly and transiently upregulated in NK cells undergoing expansion in the context of development in the bone marrow, or viral infection in the periphery. Further, our preliminary studies indicate that Birc5-deficiency severely impairs mouse NK cell development and maturation. The specific cellular functions of Birc5 in NK cells, as well as its roles in homeostatic- and infection-related NK cell expansion remain to be defined. Thus, we will conduct studies that test the central hypothesis that Birc5 acts downstream of key cytokine and metabolic growth signals to orchestrate NK cell expansion during development and peripheral immunity. These studies will utilize novel transgenic mice, in which the Birc5 gene can be deleted in NK cells in a cell-specific or conditional manner, to investigate the contributions of Birc5 to NK cell proliferation, survival, and metabolic function in settings of development, homeostatic expansion, and anti-viral immune responses in vivo. Further, we will combine sophisticated molecular and genetic techniques to define the environmental cues and intracellular signaling networks that modulate Birc5 function in NK cells. And finally, we will use an innovative mouse xenograft model to study Birc5 function in human NK cells in vivo. Ultimately, our studies have the potential to inform ongoing and future NK cell-based immunotherapies, including adoptive cell transfer (ACT) and hematopoietic stem cell transfer (HSCT) regimens that harness the anti-tumor properties of NK cells to treat cancer. !