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上皮细胞 HNF4A 通过直接调节免疫信号分子来塑造上皮内淋巴细胞区室。

Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules.

机构信息

Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA.

Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ.

出版信息

J Exp Med. 2022 Aug 1;219(8). doi: 10.1084/jem.20212563. Epub 2022 Jul 6.

DOI:10.1084/jem.20212563
PMID:35792863
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9263552/
Abstract

Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC-IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαβ+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A-BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC-IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.

摘要

肝细胞核因子 4α（HNF4A）是一种高度保守的核受体，与溃疡性结肠炎有关。在小鼠中，HNF4A 对于维持肠道内稳态是不可或缺的，但潜在的机制尚未得到很好的描述。在这里，我们证明了肠道上皮细胞（IEC）中 HNF4A 的表达对于上皮内淋巴细胞（IEL）区室的正常发育和组成是必需的。HNF4A 直接调节免疫信号分子的表达，包括 butyrophilin-like（Btnl）1、Btnl6、H2-T3 和 Clec2e，这些分子控制着 IEC-IEL 的串扰。HNF4A 选择性地增强了 TCRγδ+或 TCRαβ+CD8αα+天然 IEL 的扩增，从而塑造了 IEL 区室的组成。在小肠中，HNF4A 与其同源物 HNF4G 合作，驱动免疫信号分子的表达。此外，HNF4A-BTNL 调节轴在人类 IEC 中是保守的。总之，这些发现强调了 HNF4A 作为一种保守的转录因子控制 IEC-IEL 串扰的重要性，并表明 HNF4A 通过调节 IEL 区室维持肠道内稳态。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/b0fb34004c5b/JEM_20212563_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/876ee0d0bdb0/JEM_20212563_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/186f53bb94bc/JEM_20212563_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/b080f170d4ed/JEM_20212563_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/ee67127abdbc/JEM_20212563_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/311c06872c1e/JEM_20212563_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/e679d7a0f531/JEM_20212563_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/2e4d12591067/JEM_20212563_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/d4032d8b40c4/JEM_20212563_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/b0fb34004c5b/JEM_20212563_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/876ee0d0bdb0/JEM_20212563_GA.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/186f53bb94bc/JEM_20212563_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/b080f170d4ed/JEM_20212563_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/ee67127abdbc/JEM_20212563_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/311c06872c1e/JEM_20212563_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/e679d7a0f531/JEM_20212563_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/2e4d12591067/JEM_20212563_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/d4032d8b40c4/JEM_20212563_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9e55/9263552/b0fb34004c5b/JEM_20212563_FigS3.jpg

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