Group 2 innate lymphoid cells (ILC2s) manifest tissue heterogeneity and are crucial modulators of regional immune responses. The molecular mechanisms regulating tissue ILC2 properties remain elusive. Here, we interrogate the signatures of ILC2s from five tissues at the transcriptome and epigenetic level. We have found that tissue microenvironment strongly shapes ILC2 identities. The intestine induces Aiolos⁺ILC2s, whereas lung and pancreas enhance Galectin-1⁺ILC2s. Though being a faithful gut ILC2 feature under the steady state, Aiolos is induced in non-intestinal ILC2s by pro-inflammatory cytokines. Specifically, IL-33 stimulates Aiolos expression in both human and mouse non-intestinal ILC2s. Functionally, Aiolos facilitates eosinophil recruitment by supporting IL-5 production and proliferation of ST2⁺ILC2s through inhibiting PD-1. At the epigenetic level, ILC2 tissue characters are imprinted by open chromatin regions (OCRs) at non-promoters. Intestinal-specific transcription factor aryl hydrocarbon receptor (Ahr) binds to Ikzf3 (encoding Aiolos) locus, increases the accessibility of an intestinal ILC2-specific OCR, and promotes the Ikzf3 transcription by enhancing H3K27ac. Consequently, Ahr prevents ILC2s entering an “exhausted-like” state through sustaining Aiolos expression. Our work elucidates mechanism of ILC2 tissue adaptation and highlights Aiolos as a potential target of type 2 inflammation.

第 2 组先天性淋巴样细胞 (ILC2s) 表现出组织异质性，是区域免疫反应的关键调节剂。调节组织 ILC2 特性的分子机制仍然难以捉摸。在这里，我们在转录组和表观遗传水平上询问了来自五个组织的 ILC2 的特征。我们发现组织微环境强烈塑造了 ILC2 身份。肠道诱导 Aiolos ⁺ ILC2s，而肺和胰腺增强 Galectin-1 ⁺ILC2s。虽然 Aiolos 在稳定状态下是一个忠实的肠道 ILC2 特征，但它在非肠道 ILC2 中被促炎细胞因子诱导。具体而言，IL-33 刺激人和小鼠非肠道 ILC2 中的 Aiolos 表达。在功能上，Aiolos 通过抑制 PD-1 支持 IL-5 的产生和 ST2 ⁺ ILC2 的增殖，从而促进嗜酸性粒细胞募集。在表观遗传水平上，ILC2 组织特征由非启动子处的开放染色质区域 (OCR) 印记。肠道特异性转录因子芳烃受体 (Ahr) 与Ikzf3（编码 Aiolos）基因座结合，增加肠道 ILC2 特异性 OCR 的可及性，并促进Ikzf3通过增强 H3K27ac 进行转录。因此，Ahr 通过维持 Aiolos 表达来阻止 ILC2 进入“疲惫样”状态。我们的工作阐明了 ILC2 组织适应的机制，并强调 Aiolos 是 2 型炎症的潜在靶点。