Research ArticleINNATE LYMPHOID CELLS

A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut

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Science Immunology  04 Oct 2019:
Vol. 4, Issue 40, eaax1215
DOI: 10.1126/sciimmunol.aax1215

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Keeping track of time

A number of bodily functions, from feeding to sleeping, are regulated by our circadian clocks. Teng et al. and Wang et al. report that expression of a number of genes in intestinal group 3 innate lymphoid cells (ILC3s) in mice is synchronized to the time of day. To probe the role of clock proteins in regulating ILC3 functions, the two groups studied mice lacking distinct clock proteins, BMAL1 and REV-ERBα. Both groups found that the loss of these clock proteins resulted in marked losses of intestinal ILC3s, but that these ILC3s produced higher levels of certain cytokines. How clock proteins fit within the larger network of transcription factors in regulating development and gene expression in ILC3s remains to be seen.

Abstract

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.

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