Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity.
Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity.
复制标题
DOI：
10.1038/s41385-021-00431-5
复制
发表时间：
2021-11
影响因子：
8
通讯作者：
Qiu J
中科院分区：
文献类型：
--
作者：
Qiu J;Zhang J;Ji Y;Sun H;Gu Z;Sun Q;Bai M;Gong J;Tang J;Zhang Y;Li S;Shao Z;Li J;Sheng H;Shen L;Qiu J
第2组先天性淋巴样细胞（ILC 2）表现出组织异质性，是区域免疫应答的重要调节剂。调节组织ILC 2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来自五种组织的ILC 2的签名。我们已经发现，组织微环境强烈塑造ILC 2身份。肠诱导Aiolos+ ILC 2，而肺和胰腺增强半乳糖凝集素-1 + ILC 2。虽然在稳态下是忠实的肠道ILC 2特征，但Aiolos在非肠道ILC 2中由促炎细胞因子诱导。具体地，IL-33刺激人和小鼠非肠ILC 2两者中的Aiolos表达。在功能上，Aiolos通过抑制PD-1支持IL-5产生和ST 2 + ILC 2增殖来促进嗜酸性粒细胞募集。在表观遗传水平上，ILC 2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Ikzf 3（编码Aiolos）位点结合，增加肠道ILC 2特异性OCR的可及性，并通过增强H3 K27 ac促进Ikzf 3转录。因此，Ahr通过维持Aiolos表达来防止ILC 2进入“耗尽样”状态。我们的工作阐明了ILC 2组织适应的机制，并强调Aiolos是2型炎症的潜在靶点。
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.
登录
查看更多内容
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
12.3
作者：
Bao X;Rubin AJ;Qu K;Zhang J;Giresi PG;Chang HY;Khavari PA
通讯作者：
Khavari PA
影响因子：
14.2
作者：
Fang，Lei;Li，Junling;Roth，Michael
通讯作者：
Roth，Michael
影响因子：
32.4
作者：
Bernink, Jochem H.;Krabbendam, Lisette;Spits, Hergen
通讯作者：
Spits, Hergen
影响因子：
32.4
作者：
Halim, Timotheus Y. F.;Krauss, Ramona H.;Takei, Fumio
通讯作者：
Takei, Fumio