von Moltke Jakob, O'Leary Claire E, Barrett Nora A, Kanaoka Yoshihide, Austen K Frank, Locksley Richard M
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143.
J Exp Med. 2017 Jan;214(1):27-37. doi: 10.1084/jem.20161274. Epub 2016 Dec 23.
Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33- and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.
第2组固有淋巴细胞（ILC2s）和2型辅助性T细胞（Th2细胞）是肺部2型（过敏性）炎症期间白细胞介素5（IL-5）和IL-13的主要来源。在Th2细胞中，T细胞受体（TCR）信号激活转录因子活化T细胞核因子（NFAT）、核因子κB（NF-κB）和活化蛋白1（AP-1）以诱导2型细胞因子。ILC2s缺乏TCR，而是对局部产生的细胞因子如IL-33作出反应。虽然IL-33可诱导AP-1和NF-κB，但尚未在ILC2s中描述NFAT信号传导。在本研究中，我们报告了脂质衍生的白三烯（LTs）在肺ILC2s激活中具有非冗余的NFAT依赖性作用。使用细胞因子报告基因和LT缺陷小鼠，我们发现在2型炎症期间，LT信号的完全破坏显著减少ILC2激活和下游反应。在IL-33和LT缺陷小鼠中，2型反应同样减弱，并且最佳的ILC2激活反映了这些途径之间的强大协同作用。这些发现扩展了我们对ILC2调节的理解，并且可能对气道疾病的治疗具有重要意义。
