The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4(+) eosinophils unique to the small intestine.
The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4(+) eosinophils unique to the small intestine.
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DOI：
10.1073/pnas.2204557119
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发表时间：
2022-06-07
影响因子：
11.1
通讯作者：
Colonna, Marco
中科院分区：
文献类型：
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作者：
Wang, Wei-Le;Kasamatsu, Jun;Joshita, Satoru;Gilfillan, Susan;Di Luccia, Blanda;Panda, Santosh K;Kim, Do-Hyun;Desai, Pritesh;Bando, Jennifer K;Huang, Stanley Ching-Cheng;Yomogida, Kentaro;Hoshino, Hitomi;Fukushima, Mana;Jacobsen, Elizabeth A;Van Dyken, Steven J;Ruedl, Christiane;Cella, Marina;Colonna, Marco
嗜酸性粒细胞有助于对抗蠕虫和过敏原的2型免疫。小肠内存在嗜酸性粒细胞，其病理生理作用尚不完全清楚。在这里，我们表明，肠道嗜酸性粒细胞包括两个子集。一种表达抑制性受体Clec4a4和抑制性配体PD-L1，并且是小肠所特有的;另一种表现出促炎表型。这两个子集都是血液来源的。值得注意的是，Clec4a4+嗜酸性粒细胞由芳香烃受体（AHR）指示，芳香烃受体是一种配体激活的转录因子，可标记许多肠道免疫细胞。嗜酸性粒细胞中的选择性AHR缺失耗尽Clec4a4+嗜酸性粒细胞，增强产生2型细胞因子的先天性淋巴细胞，并增强蠕虫清除。我们的结论是，Clec4a4+嗜酸性粒细胞具有免疫调节功能，这可以用于治疗食物过敏和嗜酸性胃肠疾病。C型凝集素结构域家族4，成员a4（Clec4a4）是一种C型凝集素抑制性受体，对聚糖具有特异性，被认为仅在鼠CD8 α −常规树突状细胞上表达。使用新产生的Clec4a4-mCherry敲入小鼠，我们鉴定了一个独特地定位于小肠固有层中的表达Clec4a4的嗜酸性粒细胞的子集。Clec4a4+嗜酸性粒细胞表现出免疫调节特征，而Clec4a4 −嗜酸性粒细胞表现出促炎特征。Clec4a4+嗜酸性粒细胞表达高水平的芳烃受体（Ahr），这驱动了Clec4a4以及其他免疫调节特征（如PD-L1）的表达。Clec4a4+嗜酸性粒细胞的丰度依赖于饮食AHR配体，随着年龄的增长而增加，并在炎症条件下下降。嗜酸性粒细胞中缺乏AHR的小鼠比野生型小鼠更有效地扩增了2型先天淋巴细胞并清除了巴西日本圆线虫感染。这些结果突出了嗜酸性粒细胞对组织线索的反应的异质性，并确定了具有免疫调节特征的小肠中嗜酸性粒细胞的独特AHR依赖性亚群。
Eosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4+ eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4+ eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4+ eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders. C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.