Transcription Factors that Specify Natural Killer Cell Fate and Function

描述（由申请人提供）：自然杀伤（NK）细胞是参与针对病毒、细菌、寄生虫、肿瘤和移植的免疫反应的淋巴细胞。它们的发育可以分为遗传上可分离的阶段，由T-box转录因子T-bet和eomesdermin （Eomes）控制。NK细胞长期以来一直被归类为先天免疫细胞，因为它们缺乏组装各种T和b淋巴细胞抗原受体所必需的蛋白质的表达。NK细胞以与其他淋巴细胞不同的方式区分健康和有害的体细胞，但它们是如何在发育过程中被教育来进行这种区分的，目前还不完全清楚。该项目旨在扩大我们目前对形成NK细胞成熟到不同阶段的信号的理解，并在适当的情况下进行必要的教育，以参与免疫防御。第一个目的是确定NK细胞的成熟是否可以通过条件过表达T-bet来阻止，T-bet是一种与未成熟NK细胞的维持相关的转录因子。第二个目标将采用转基因小鼠模型，其中Eomes在T-bet调控元件的控制下异位表达，以检查在通常缺乏成熟NK细胞的器官中强迫NK细胞过早成熟是否会干扰NK细胞的教育、自我耐受性和功能。第三个目标将利用T-bet和Eomes缺陷的各种遗传模型来评估这些转录因子在动员NK细胞召回反应中的潜在作用。这些目标的成功实现可能会促进NK细胞治疗癌症和传染病的发展。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are lymphocytes that participate in the immune response against viruses, bacteria, parasites, tumors, and transplants. Their development can be classified into genetically separable stages that are governed by the T-box transcription factors T-bet and Eomesodermin (Eomes). NK cells have long been categorized as innate immune cells because they lack expression of the proteins that are necessary to assemble diverse T- and B-lymphocyte antigen receptors. NK cells discriminate between healthy and harmful somatic cells in a different manner from other lymphocytes, but how they become educated to make this distinction during development is not completely understood. This project, in 3 aims, seeks to expand on our current understanding of the signals that shape the maturation of NK cells to distinct stages with the necessary education to partake in immune defense under the right circumstances. The first aim will determine whether NK cell maturation can be blocked by conditional overexpression of T-bet, a transcription factor that is associated with the maintenance of immature NK cells. The second aim will employ a transgenic mouse model, in which Eomes is ectopically expressed under the control of T-bet regulatory elements, to examine whether forcing precocious NK cell maturation in organs typically devoid of mature NK cells will perturb NK cell education, self-tolerance, and function. The third aim will utilize various genetic models of T-bet and Eomes deficiency to assess the potential role of these transcription factors in mobilizing NK cell recall responses. The successful execution of these aims may promote the development of NK cell therapies against cancer and infectious diseases.