Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
J Exp Med. 2011 Mar 14;208(3):593-604. doi: 10.1084/jem.20100793. Epub 2011 Feb 28.
The innate signaling pathways for Th2 immunity activated by inhaled antigens are not well defined. We previously identified Dectin-2 as a receptor for glycans in allergen extracts from the house dust mite Dermatophagoides farinae (Df) that mediates cysteinyl leukotriene (cys-LT) generation from pulmonary CD11c+ cells and from GM-CSF-cultured bone marrow cells (BMCs(GM-CSF)). Using lentiviral knockdown of Dectin-2 in BMCs(GM-CSF) and adoptive transfer of Df-pulsed BMCs(GM-CSF) to sensitize naive mice, we now report that Dectin-2 is critical for the development of Df-elicited eosinophilic and neutrophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Sensitization with Df-pulsed BMCs(GM-CSF) from LTC(4) synthase (LTC(4)S)-deficient mice or type 1 cys-LT receptor (CysLT1R)-deficient mice demonstrated that both proteins were required for Df-elicited eosinophilic pulmonary inflammation and Th2 cytokine generation in the lungs and restimulated lymph nodes. Direct sensitization and challenge of Ltc4s-/- and Cysltr1-/- mice confirmed that cys-LTs mediate these parameters of Df-elicited Th2 pulmonary inflammation. Thus, the Dectin-2-cys-LT pathway is critical for the induction of Th2 immunity to a major allergen, in part through CysLT1R. These findings identify a previously unrecognized link between a myeloid C-type lectin receptor and Th2 immunity.
先天的 Th2 免疫信号通路被吸入的抗原激活的机制尚未完全明确。我们之前发现 Dectin-2 是屋尘螨（Dermatophagoides farinae，Df）过敏原提取物中糖链的受体，它介导半胱氨酰白三烯（cys-LT）从肺部 CD11c+细胞和 GM-CSF 培养的骨髓细胞（BMCs(GM-CSF)）中产生。通过使用慢病毒敲低 BMCs(GM-CSF)中的 Dectin-2 以及过继转移 Df 脉冲刺激的 BMCs(GM-CSF)来致敏初始小鼠，我们现在报告 Dectin-2 对于 Df 诱导的嗜酸性粒细胞和中性粒细胞性肺部炎症以及肺部和再刺激淋巴结中 Th2 细胞因子的产生至关重要。用来自 LTC(4)合酶（LTC(4)S）缺陷型小鼠或 1 型 cys-LT 受体（CysLT1R）缺陷型小鼠的 Df 脉冲刺激的 BMCs(GM-CSF)进行致敏表明，这两种蛋白对于 Df 诱导的肺部嗜酸性粒细胞炎症和肺部和再刺激淋巴结中的 Th2 细胞因子产生都是必需的。Ltc4s-/-和 Cysltr1-/-小鼠的直接致敏和挑战证实 cys-LTs 介导了 Df 诱导的 Th2 肺部炎症的这些参数。因此，Dectin-2-cys-LT 通路对于诱导对主要过敏原的 Th2 免疫至关重要，部分是通过 CysLT1R。这些发现确定了一个以前未被识别的骨髓细胞 C 型凝集素受体和 Th2 免疫之间的联系。
