1 Respiratory, Inflammation and Autoimmunity, MedImmune Ltd., Cambridge, United Kingdom.
2 Research Service, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan.
Am J Respir Crit Care Med. 2018 Nov 1;198(9):1140-1150. doi: 10.1164/rccm.201712-2513OC.
Lung natural killer cells (NKs) kill a greater percentage of autologous lung parenchymal cells in chronic obstructive pulmonary disease (COPD) than in nonobstructed smokers. To become cytotoxic, NKs require priming, typically by dendritic cells (DCs), but whether priming occurs in the lungs in COPD is unknown.
We used lung tissue and in some cases peripheral blood from patients undergoing clinically indicated resections to determine in vitro killing of CD326 lung epithelial cells by isolated lung CD56 NKs. We also measured the cytotoxicity of unprimed blood NKs after preincubation with lung DCs. To investigate mechanisms of DC-mediated priming, we used murine models of COPD induced by cigarette smoke (CS) exposure or by polymeric immunoglobulin receptor (pIgR) deficiency, and blocked IL-15Rα (IL-15 receptor α subunit) trans-presentation by genetic and antibody approaches.
Human lung NKs killed isolated autologous lung epithelial cells; cytotoxicity was increased (P = 0.0001) in COPD, relative to smokers without obstruction. Similarly, increased lung NK cytotoxicity compared with control subjects was observed in CS-exposed mice and pIgR mice. Blood NKs both from smokers without obstruction and subjects with COPD showed minimal epithelial cell killing, but in COPD, preincubation with lung DCs increased cytotoxicity. NKs were primed by CS-exposed murine DCs in vitro and in vivo. Inhibiting IL-15Rα trans-presentation eliminated NK priming both by murine CS-exposed DCs and by lung DCs from subjects with COPD.
Heightened NK cytotoxicity against lung epithelial cells in COPD results primarily from lung DC-mediated priming via IL-15 trans-presentation on IL-15Rα. Future studies are required to test whether increased NK cytotoxicity contributes to COPD pathogenesis.
与非阻塞性吸烟者相比，慢性阻塞性肺疾病（COPD）患者的肺自然杀伤细胞（NK 细胞）杀死更多的自体肺实质细胞。为了成为细胞毒性细胞，NK 细胞需要激活，通常由树突状细胞（DC）激活，但在 COPD 中，肺内是否发生激活尚不清楚。
我们使用了来自接受临床指示性切除术的患者的肺组织和在某些情况下的外周血，以确定分离的肺 CD56NK 细胞对 CD326 肺上皮细胞的体外杀伤作用。我们还测量了未经预处理的血液 NK 细胞在与肺 DC 预孵育后的细胞毒性。为了研究 DC 介导的激活机制，我们使用了香烟烟雾（CS）暴露或多聚免疫球蛋白受体（pIgR）缺乏诱导的 COPD 小鼠模型，并通过遗传和抗体方法阻断了白细胞介素-15 受体α（IL-15 受体 α 亚基）的转呈递。
人肺 NK 细胞杀死分离的自体肺上皮细胞；与无阻塞的吸烟者相比，COPD 患者的细胞毒性增加（P = 0.0001）。同样，在 CS 暴露的小鼠和 pIgR 小鼠中也观察到与对照相比，肺 NK 细胞的细胞毒性增加。来自无阻塞性吸烟者和 COPD 患者的血液 NK 细胞对上皮细胞的杀伤作用均较小，但在 COPD 患者中，与肺 DC 预孵育可增加细胞毒性。CS 暴露的小鼠 DC 体外和体内均可激活 NK 细胞。抑制白细胞介素-15Rα 的转呈递消除了 CS 暴露的小鼠 DC 和 COPD 患者肺 DC 对 NK 细胞的激活。
COPD 患者对肺上皮细胞的 NK 细胞细胞毒性增加主要是由于 IL-15 通过 IL-15Rα 的转呈递由肺 DC 介导的激活所致。需要进一步的研究来测试 NK 细胞的增加的细胞毒性是否有助于 COPD 的发病机制。
