Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.

皮肤第 2 组先天淋巴细胞 (ILC2) 在空间和表观遗传上做好了应对屏障受损和相关免疫威胁的准备。 ILC2 缺乏重排的抗原特异性受体，主要由损伤相关细胞因子激活，并通过 2 型细胞因子的产生做出反应。为了研究 ILC2 直接感测皮肤病原体和过敏原的潜力，我们对来自体内受挑战的人类皮肤或血液的 ILC2 进行了 RNA 测序。我们通过皮肤和血液ILC2检测NOD2和TLR2的表达。单独用 TLR2 激动剂刺激 ILC2 不仅诱导白细胞介素 5 (IL-5) 和 IL-13 表达，而且与金黄色葡萄球菌胞壁酰二肽 (MDP) 联合诱导 IL-6 表达。热灭活的皮肤驻留细菌在体外激发了 ILC2 中的 IL-6 谱，而来自含有核苷酸结合寡聚化结构域的蛋白 2 (NOD2)突变的患者的 ILC2 中的 IL-6 谱明显受损。此外，我们发现NOD2信号传导可以刺激 ILC2 的自噬，而 ILC2 在NOD2突变的患者中也受到损害。在这里，我们已经确定了 ILC2 NOD2 信号传导在 ILC2 衍生的 IL-6 差异调节中的作用，并报告了以前未被识别的直接 ILC2 细菌传感途径。