华盛顿大学医学院Marco Colonna课题组取得一项新突破。他们发现了昼夜节律回路通过维持RORγt的表观遗传结构来控制第3组先天淋巴样细胞的可塑性。这一研究成果发表在2025年8月13日出版的国际学术期刊《自然—免疫学》上。

在这里，课题组研究人员发现昼夜节律蛋白REV-ERBα和REV-ERBβ维持ILC3的身份。它们的联合缺失促进了ILC3到ILC1的转化，降低了能量代谢和IL-22的产生，增加了干扰素γ的产生，并提高了对鼠柠檬酸杆菌感染的易感性。单细胞多组学和基因编辑发现，REV-ERBα /REV-ERBβ缺乏上调转录因子NFIL3，通过Rorc基因中- 2 kb的顺式调控元件抑制RORγt的表达，使细胞转向T-bet驱动状态。染色质和代谢分析表明，REV-ERBα/REV-ERBβ的缺失重新编程了调节和代谢回路。其中，REV-ERBα/REV-ERBβ通过调节控制RORγt表达的时钟基因，保护肠道完整性，保持ILC3的特性和对肠道炎症的抵抗力。

据介绍，肠道每天都会经历微生物和营养物质的波动，这些波动与调节营养吸收和免疫功能的昼夜节律一致。第3组先天淋巴样细胞（ILC3s）通过白细胞介素-22 （IL-22）支持肠道稳态，但可以转化为产生干扰素-γ的ILC1s。昼夜节律蛋白如何控制这种可塑性尚不清楚。

附：英文原文

Title: Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt

Author: Bhattarai, Bishan, Antonova, Alina Ulezko, Fachi, Jose L., Hopkins, Leone S., McCullen, Matthew V. D., Saini, Ankita, Oliveira, Sarah de, Beatty, Wandy L., Musiek, Erik S., Kuchroo, Vijay K., Lazar, Mitchell A., Oltz, Eugene M., Colonna, Marco

Issue&Volume: 2025-08-13

Abstract: The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a –2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.

DOI: 10.1038/s41590-025-02240-5

Source: https://www.nature.com/articles/s41590-025-02240-5