Michel Marie-Laure, Keller Alexandre Castro, Paget Christophe, Fujio Masakazu, Trottein François, Savage Paul B, Wong Chi-Huey, Schneider Elke, Dy Michel, Leite-de-Moraes Maria C
Unité Mixte de Recherche 8147, Centre National de la Recherche Scientifique, Faculté de Médecine René Descartes, Paris V, Hôpital Necker, Paris, Cedex 15, France.
J Exp Med. 2007 May 14;204(5):995-1001. doi: 10.1084/jem.20061551. Epub 2007 Apr 30.
Invariant natural killer T (iNKT) cells are an important source of both T helper type 1 (Th1) and Th2 cytokines, through which they can exert beneficial, as well as deleterious, effects in a variety of inflammatory diseases. This functional heterogeneity raises the question of how far phenotypically distinct subpopulations are responsible for such contrasting activities. In this study, we identify a particular set of iNKT cells that lack the NK1.1 marker (NK1.1(neg)) and secrete high amounts of interleukin (IL)-17 and low levels of interferon (IFN)-gamma and IL-4. NK1.1(neg) iNKT cells produce IL-17 upon synthetic (alpha-galactosylceramide [alpha-GalCer] or PBS-57), as well as natural (lipopolysaccharides or glycolipids derived from Sphingomonas wittichii and Borrelia burgdorferi), ligand stimulation. NK1.1(neg) iNKT cells are more frequent in the lung, which is consistent with a role in the natural immunity to inhaled antigens. Indeed, airway neutrophilia induced by alpha-GalCer or lipopolysaccharide instillation was significantly reduced in iNKT-cell-deficient Jalpha18(-/-) mice, which produced significantly less IL-17 in their bronchoalveolar lavage fluid than wild-type controls. Furthermore, airway neutrophilia was abolished by a single treatment with neutralizing monoclonal antibody against IL-17 before alpha-GalCer administration. Collectively, our findings reveal that NK1.1(neg) iNKT lymphocytes represent a new population of IL-17-producing cells that can contribute to neutrophil recruitment through preferential IL-17 secretion.
不变自然杀伤T（iNKT）细胞是1型辅助性T细胞（Th1）和Th2细胞因子的重要来源，通过它们在多种炎症性疾病中可发挥有益和有害作用。这种功能异质性引发了一个问题，即表型不同的亚群在多大程度上导致了这种相反的活性。在本研究中，我们鉴定出一组特定的iNKT细胞，它们缺乏NK1.1标记（NK1.1阴性），分泌大量白细胞介素（IL）-17，低水平干扰素（IFN）-γ和IL-4。NK1.1阴性iNKT细胞在合成配体（α-半乳糖神经酰胺[α-GalCer]或PBS-57）以及天然配体（脂多糖或源自维氏鞘氨醇单胞菌和伯氏疏螺旋体的糖脂）刺激下产生IL-17。NK1.1阴性iNKT细胞在肺中更为常见，这与它们在对吸入抗原的天然免疫中的作用一致。实际上，在iNKT细胞缺陷的Jα18（-/-）小鼠中，由α-GalCer或脂多糖滴注诱导的气道中性粒细胞增多显著减少，其支气管肺泡灌洗液中产生的IL-17明显少于野生型对照。此外，在给予α-GalCer之前，用抗IL-17的中和单克隆抗体进行单次治疗可消除气道中性粒细胞增多。总的来说，我们的研究结果表明，NK1.1阴性iNKT淋巴细胞代表了一群新的产生IL-17的细胞，它们可通过优先分泌IL-17促进中性粒细胞募集。
