Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases.
Patrolling Monocytes Control NK Cell Expression of Activating and Stimulatory Receptors to Curtail Lung Metastases.
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DOI：
10.4049/jimmunol.1900998
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发表时间：
2020-01-01
期刊：
影响因子：
--
通讯作者：
Hedrick CC
中科院分区：
文献类型：
--
作者：
Narasimhan PB;Eggert T;Zhu YP;Marcovecchio P;Meyer MA;Wu R;Hedrick CC
非经典的巡逻单核细胞在肺肿瘤转移中的作用及其与其他免疫细胞的功能关系仍不清楚。造成这些知识空白的原因是在用于消耗非经典单核细胞的常用方法中缺乏细胞特异性。为了规避这些限制并研究巡逻单核细胞在黑色素瘤转移到肺中的作用，我们产生了一种小鼠品系，其中Nr 4a 1超级增强子E2亚结构域被消融（E2−/−小鼠）。E2−/−小鼠缺乏巡逻单核细胞，但保留了巨噬细胞的数量和功能。有趣的是，自然杀伤（NK）细胞的募集和激活受到损害，而E2−/−小鼠的转移负荷增加。此外，E2−/−小鼠显示出“受过教育”（CD 11b + CD 27+）和“终末分化”（CD 11b + CD 27 −）的NK细胞频率没有变化。这些扰动伴随着受教育的NK细胞上刺激性受体Ly 49 D的表达减少和终末分化的NK细胞上抑制性受体NKG 2A/CD 94的表达增加。因此，我们的工作表明，巡逻单核细胞通过NK细胞募集和激活在预防肺肿瘤转移中发挥关键作用。
The role of non-classical, patrolling monocytes in lung tumor metastasis and their functional relationships with other immune cells remain poorly defined. Contributing to these gaps in knowledge is a lack of cellular specificity in commonly used approaches for depleting non-classical monocytes. To circumvent these limitations and study the role of patrolling monocytes in melanoma metastasis to lungs, we generated a mouse strain in which the Nr4a1 super-enhancer E2 subdomain is ablated (E2−/− mice). E2−/− mice lack patrolling monocytes but preserve macrophage numbers and functions. Interestingly, natural killer (NK) cell recruitment and activation were impaired, while metastatic burden was increased in E2−/−mice. Moreover, E2−/− mice displayed unchanged ‘educated’ (CD11b+CD27+) and ‘terminally differentiated’ (CD11b+CD27−) NK cell frequencies. These perturbations were accompanied by reduced expression of stimulatory receptor Ly49D on educated NK cells and increased expression of inhibitory receptor NKG2A/CD94 on terminally differentiated NK cells. Thus, our work demonstrates that patrolling monocytes play a critical role in preventing lung tumor metastasis via NK cell recruitment and activation.
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