Department of Otolaryngology - Head and Neck Surgery, Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States.
Front Immunol. 2021 Feb 24;12:624284. doi: 10.3389/fimmu.2021.624284. eCollection 2021.
Natural killer (NK) cells are effector cells of the innate immune system involved in defense against virus-infected and transformed cells. The effector function of NK cells is linked to their ability to migrate to sites of inflammation or damage. Therefore, understanding the factors regulating NK cell migration is of substantial interest. Here, we show that in the absence of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, NK cells have reduced capacity to migrate and infiltrate tumors . Analysis of differentially expressed genes revealed that ankyrin repeat and SOCS Box containing 2 () expression was dramatically decreased in NK cells and that AhR ligands modulated its expression. Further, AhR directly regulated the promoter region of the gene. Similar to what was observed with murine NK cells, knockdown inhibited the migration of human NK cells. Activation of AHR by its agonist FICZ induced ASB2-dependent filamin A degradation in NK cells; conversely, knockdown of endogenous inhibited filamin A degradation. Reduction of filamin A increased the migration of primary NK cells and restored the invasion capacity of AHR-deficient NK cells. Our study introduces AHR as a new regulator of NK cell migration, through an AHR-ASB2-filamin A axis and provides insight into a potential therapeutic target for NK cell-based immunotherapies.
自然杀伤 (NK) 细胞是先天免疫系统的效应细胞，参与防御病毒感染和转化细胞。NK 细胞的效应功能与其向炎症或损伤部位迁移的能力有关。因此，了解调节 NK 细胞迁移的因素具有重要意义。在这里，我们表明在缺乏芳基烃受体 (AHR) 的情况下，一种配体激活的转录因子，NK 细胞的迁移和浸润肿瘤的能力降低。差异表达基因分析表明，锚蛋白重复和含 SOCS 框的 2 () 的表达在 NK 细胞中显著降低，AHR 配体调节其表达。此外，AHR 直接调节 基因的启动子区域。与在鼠 NK 细胞中观察到的情况类似， 敲低抑制了人 NK 细胞的迁移。其激动剂 FICZ 激活 AHR 诱导 NK 细胞中 ASB2 依赖性细丝蛋白 A 降解；相反，内源性 的敲低抑制了细丝蛋白 A 的降解。纤连蛋白 A 的减少增加了原代 NK 细胞的迁移，并恢复了 AHR 缺陷型 NK 细胞的侵袭能力。我们的研究通过 AHR-ASB2-细丝蛋白 A 轴将 AHR 介绍为 NK 细胞迁移的新调节剂，并为基于 NK 细胞的免疫疗法的潜在治疗靶点提供了新的见解。
