Group 3 innate lymphoid cells (ILC3s) critically orchestrate host-microbe interactions in the healthy mammalian intestine and become substantially impaired in the context of inflammatory bowel disease (IBD). However, the molecular pathways controlling the homeostasis of ILC3s remain incompletely defined. Here, we identify that intestinal ILC3s are highly enriched in expression of genes involved in the circadian clock and exhibit diurnal oscillations of these pathways in response to light cues. Classical ILC3 effector functions also exhibited diurnal oscillations, and lineage-specific deletion of BMAL1, a master regulator of the circadian clock, resulted in markedly reduced ILC3s selectively in the intestine. BMAL1-deficient ILC3s exhibit impaired expression of Nr1d1 and Per3, hyperactivation of RORγt-dependent target genes, and elevated proapoptotic pathways. Depletion of the microbiota with antibiotics partially reduced the hyperactivation of BMAL1-deficient ILC3s and restored cellular homeostasis in the intestine. Last, ILC3s isolated from the inflamed intestine of patients with IBD exhibit substantial alterations in expression of several circadian-related genes. Our results collectively define that circadian regulation is essential for the homeostasis of ILC3s in the presence of a complex intestinal microbiota and that this pathway is disrupted in the context of IBD.

中文翻译：

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生物钟对于肠道中第 3 组先天淋巴细胞的稳态至关重要。


第 3 组先天淋巴细胞 (ILC3) 在健康哺乳动物肠道中关键地协调宿主-微生物相互作用，并在炎症性肠病 (IBD) 的情况下受到严重损害。然而，控制 ILC3 稳态的分子途径仍未完全确定。在这里，我们发现肠道 ILC3 高度丰富地表达与生物钟相关的基因，并表现出这些途径响应光信号的昼夜振荡。经典的 ILC3 效应器功能也表现出昼夜振荡，并且生物钟主调节器 BMAL1 的谱系特异性缺失导致肠道中 ILC3 选择性显着减少。 BMAL1 缺陷的 ILC3 表现出 Nr1d1 和 Per3 表达受损、RORγt 依赖性靶基因过度激活以及促凋亡途径升高。用抗生素消除微生物群可部分减少 BMAL1 缺陷型 ILC3 的过度激活，并恢复肠道内的细胞稳态。最后，从 IBD 患者发炎肠道中分离出的 ILC3 表现出多种昼夜节律相关基因表达的显着改变。我们的结果共同表明，在复杂的肠道微生物群存在的情况下，昼夜节律调节对于 ILC3 的稳态至关重要，并且该途径在 IBD 的背景下被破坏。