Valayer Alexandre, Brea Deborah, Lajoie Laurie, Avezard Leslie, Combes-Soia Lucie, Labas Valerie, Korkmaz Brice, Thibault Gilles, Baranek Thomas, Si-Tahar Mustapha
Université François Rabelais de Tours, Tours, France.
Institut National de la Santé et de la Recherche Médicale, Centre d'Etude des Pathologies Respiratoires, Unite Mixte de Recherche 1100, Tours, France.
J Leukoc Biol. 2017 Jan;101(1):253-259. doi: 10.1189/jlb.3AB0316-140RR. Epub 2016 Sep 1.
Polymorphonuclear neutrophils (PMNs) can contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Mechanisms by which this immunoregulation process occurs remain incompletely understood. Here, we focused on the effect of human neutrophil-derived serine proteases on NKp46, a crucial activating receptor expressed on NK cells. We used flow cytometry, Western blotting, and mass spectrometry (MS) analysis to reveal that cathepsin G [CG; and not elastase or proteinase 3 (PR3)] induces a time- and concentration-dependent, down-regulatory effect on NKp46 expression through a restricted proteolytic mechanism. We also used a functional assay to demonstrate that NKp46 cleavage by CG severely impairs NKp46-mediated responses of NK cells, including IFN-γ production and cell degranulation. Importantly, sputa of cystic fibrosis (CF) patients, which have high concentrations of CG, also alter NKp46 on NK cells. Hence, we have identified a new immunoregulatory mechanism of neutrophils that proteolytically disarms NK cell responses.
多形核中性粒细胞（PMNs）可通过与包括自然杀伤细胞（NK细胞）在内的先天性和适应性白细胞相互作用，参与宿主免疫反应的调节。这种免疫调节过程发生的机制仍未完全清楚。在此，我们聚焦于人类中性粒细胞衍生的丝氨酸蛋白酶对NKp46的影响，NKp46是NK细胞上表达的一种关键激活受体。我们使用流式细胞术、蛋白质印迹法和质谱（MS）分析来揭示组织蛋白酶G [CG；而非弹性蛋白酶或蛋白酶3（PR3）] 通过一种有限的蛋白水解机制，对NKp46表达产生时间和浓度依赖性的下调作用。我们还使用功能测定法来证明CG对NKp46的切割严重损害了NK细胞的NKp46介导的反应，包括干扰素-γ的产生和细胞脱颗粒。重要的是，囊性纤维化（CF）患者痰液中CG浓度很高，也会改变NK细胞上的NKp46。因此，我们确定了一种新的中性粒细胞免疫调节机制，即通过蛋白水解作用解除NK细胞反应。
