Circadian rhythm–dependent and circadian rhythm–independent impacts of the molecular clock on type 3 innate lymphoid cells

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Science Immunology  04 Oct 2019:
Vol. 4, Issue 40, eaay7501
DOI: 10.1126/sciimmunol.aay7501

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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.


Many gut functions are attuned to circadian rhythm. Intestinal group 3 innate lymphoid cells (ILC3s) include NKp46+ and NKp46 subsets, which are RORγt dependent and provide mucosal defense through secretion of interleukin-22 (IL-22) and IL-17. Because ILC3s highly express some key circadian clock genes, we investigated whether ILC3s are also attuned to circadian rhythm. We noted circadian oscillations in the expression of clock and cytokine genes, such as REV-ERBα, IL-22, and IL-17, whereas acute disruption of the circadian rhythm affected cytokine secretion by ILC3s. Because of prominent and rhythmic expression of REV-ERBα in ILC3s, we also investigated the impact of constitutive deletion of REV-ERBα, which has been previously shown to inhibit the expression of a RORγt repressor, NFIL3, while also directly antagonizing DNA binding of RORγt. Development of the NKp46+ ILC3 subset was markedly impaired, with reduced cell numbers, RORγt expression, and IL-22 production in REV-ERBα–deficient mice. The NKp46 ILC3 subsets developed normally, potentially due to compensatory expression of other clock genes, but IL-17 secretion paradoxically increased, probably because RORγt was not antagonized by REV-ERBα. We conclude that ILC3s are attuned to circadian rhythm, but clock regulator REV-ERBα also has circadian-independent impacts on ILC3 development and functions due to its roles in the regulation of RORγt.

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