Gene regulatory architecture of CD56 bright natural killer cells

项目摘要 该项目的重点是基因组调节剂如何指导自然杀伤（NK）细胞控制感染， 恶性肿瘤。在这方面，具体目标是：1）确定循环和组织- 常驻“助手”样NK细胞表观遗传学上相互重塑;以及，2）确定调节过渡点 将循环中的NK细胞“锁定”在它们的细胞溶解谱系中，阻断辅助细胞的身份。 自然杀伤细胞是天生的淋巴细胞，这意味着它们可以识别并通常消除感染 和肿瘤的免疫反应之前需要产生。这种固有的功能使它们 特别可用于新一代疗法：NK细胞不能参与移植物抗宿主病 （对细胞治疗很重要），它们可以用抗体武装（抗体介导的治疗所需的）， 并迅速对环境作出反应（对细胞因子疗法很重要）。他们的誓言，在新的世纪里， 癌症和免疫治疗，更深入地了解临床有益的NK细胞表型是高 要务 不幸的是，慢性炎症可能会阻止NK细胞在用于治疗时发挥作用。因此，在本发明中， 这项计划的目的是确定炎症环境如何通过表观遗传学建立NK细胞身份， 编程.首先，我们将研究慢性炎症如何改变NK细胞表观基因组， NK细胞用于治疗的有益特征。然后我们将测定炎症期间NK细胞的异质性， 包括它们的表观遗传景观。最理想的情况是， 许多研究人员使用它来确定控制杀伤NK细胞身份的机制。事实上，由于这一过程 可能在不同的病理学中功能失调，这些数据可能对广泛的领域感兴趣。许多 感染、实体瘤和血液恶性肿瘤，如急性髓性白血病， 重新编程NK细胞因此，所确定的途径可能是有效免疫的主要障碍。

PROJECT SUMMARY This project focuses on how genomic regulators direct natural killer (NK) cells to control infections and malignancies. In this regard, the specific aims are: 1) to determine mechanisms by which circulating and tissue- resident “helper” like NK cells epigenetically remodel into each other; and, 2) identify regulatory transition points that “lock” circulating NK cells into their cytolytic lineage, blocking the helper identities. Natural killer cells are innate lymphocytes, which means they can recognize, and normally eliminate, infections and tumors before a full immune response needs to be generated. This innate functionality makes them particularly exploitable for a new generation of therapies: NK cells cannot participate in graft-versus-host disease (important for cellular therapy), they can be armed with antibodies (required for antibody-mediated therapies), and rapidly respond to their environment (important for cytokine therapies). Given their promise in novel anti- cancer and immune therapeutics, a deeper understanding of clinically beneficial NK cell phenotypes is of high priority. Unfortunately, chronic inflammation may prevent NK cells from functioning when exploited for therapies. As such, the goal of this proposal is to define how inflammatory environments establish NK cell identities, via epigenetic programming. First, We will investigate how chronic inflammation alters the NK cell epigenome, shutting down the beneficial features of NK cells used in therapy. We will then assay NK cell heterogeneity during inflammation, including their epigenetic landscape. The output will be made available as publicly available datasets, ideally used by many researchers to identify mechanisms governing killer NK cell identities. Indeed, as this process may be dysfunctional in diverse pathologies, the data could be of interest to a wide range of fields. Many infections, solid tumors and hematological malignancies, such as acute myeloid leukemia, create environments that reprogram NK cells. Thus, the identified pathways may be a major barrier to effective immunity.