Birc5 as a regulator of NK cell development and immune function

摘要 自然杀伤(NK)细胞是一种细胞毒性淋巴细胞，可介导对病毒病原体和 肿瘤。在临床环境中，NK细胞是过继细胞转移(ACT)和造血干细胞的靶点 治疗癌症和癌症相关疾病的细胞移植(HSCT)方案和免疫治疗方法 感染。有效的NK细胞免疫是建立在体内持续存在有功能的NK细胞池的基础上的 外围。在稳定状态下，新的NK细胞的不断发展维持着NK细胞的生态位 来自骨髓中的祖细胞群体和成熟的NK细胞在体内的动态平衡扩张 外围设备。此外，某些炎症信号可能会瞬间扩大效应NK细胞， 在感染或恶变期间的保护。了解控制这些过程的分子途径 将对临床上新的和更有效的基于NK细胞的疗法的发展产生关键的影响。 我们的初步研究强调了凋亡抑制蛋白(IAP)BIRC5的关键作用， 在NK细胞中的造血和功能。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，作用 通过其在细胞核、细胞质和线粒体中的高度区域化活动。一个 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具有很高的 在骨髓发育过程中经历扩增的NK细胞瞬时上调，或 外围的病毒感染。此外，我们的初步研究表明，Birc5缺乏严重损害 小鼠NK细胞的发育和成熟。BIRC5在NK细胞中的特异性细胞功能及其在细胞中的表达 在动态平衡和感染相关的NK细胞扩增中的作用仍有待确定。因此，我们将进行 测试BIRC5作用于关键细胞因子下游和代谢增长这一中心假设的研究 在发育和外周免疫过程中协调NK细胞扩张的信号。这些研究将利用 新型转基因小鼠，其中Birc5基因可在细胞特异性或条件性缺失的NK细胞中缺失 探讨BIRC5对小鼠NK细胞增殖、存活和代谢功能的影响。 体内发育、体内平衡扩张和抗病毒免疫反应的环境。此外，我们还将 结合复杂的分子和遗传技术来定义环境线索和细胞内 调节NK细胞中BIRC5功能的信号网络。最后，我们将使用一种创新的鼠标 异种移植模型研究Birc5在体内对人NK细胞的作用最终，我们的研究有可能 告知正在进行和未来基于NK细胞的免疫疗法，包括过继细胞转移(ACT)和 利用NK细胞抗肿瘤特性的造血干细胞移植(HSCT)方案治疗 癌症。 好了！

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. !