Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Keeping time in group 3 innate lymphoid cells

Nature Reviews Immunology volume 20, pages 720–726 (2020)Cite this article

Subjects

Abstract

Each day, the gastrointestinal tract encounters an influx of microbial and nutrient-derived signals and its physiological activities often adhere to a circadian rhythm. As such, group 3 innate lymphoid cells (ILC3s) that reside in the intestinal mucosa must function within a highly dynamic environment. In this Progress article, we highlight a series of recent reports that have characterized the circadian clock in ILC3s. We discuss how these studies have illustrated the roles of environmental cues and clock genes in regulating ILC3 biology and consider the implications for intestinal immunity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Transcription–translation feedback loops of the circadian clock.
Fig. 2: Circadian regulation of intestinal ILC3s in mice.

Similar content being viewed by others

References

  1. O’Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature 469, 498–503 (2011).

    PubMed  PubMed Central  Google Scholar 

  2. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    CAS  PubMed  Google Scholar 

  3. Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic-helix–loop–helix–PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    CAS  PubMed  Google Scholar 

  4. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999).

    CAS  PubMed  Google Scholar 

  6. Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000).

    CAS  PubMed  Google Scholar 

  7. Preitner, N. et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 110, 251–260 (2002).

    CAS  PubMed  Google Scholar 

  8. Sato, T. K. et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron 43, 527–537 (2004).

    CAS  PubMed  Google Scholar 

  9. Bugge, A. et al. Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function. Genes. Dev. 26, 657–667 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cho, H. et al. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. Nature 485, 123–127 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y. & Okamura, H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes. Dev. 15, 995–1006 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Ueda, H. R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).

    CAS  PubMed  Google Scholar 

  13. Bechtold, D. A. & Loudon, A. S. I. Hypothalamic clocks and rhythms in feeding behaviour. Trends Neurosci. 36, 74–82 (2013).

    CAS  PubMed  Google Scholar 

  14. Asher, G. & Sassone-Corsi, P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 161, 84–92 (2015).

    CAS  PubMed  Google Scholar 

  15. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    CAS  PubMed  Google Scholar 

  16. Robinette, M. L. et al. Transcriptional programs define molecular characteristics of innate lymphoid cell classes and subsets. Nat. Immunol. 16, 306–317 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

    CAS  PubMed  Google Scholar 

  19. Klose, C. S. N. et al. A T-bet gradient controls the fate and function of CCR6–RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).

    CAS  PubMed  Google Scholar 

  20. Rankin, L. C. et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nat. Immunol. 14, 389–395 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host–commensal symbiosis in sickness. Nature 514, 638 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009 (2014).

    PubMed  PubMed Central  Google Scholar 

  23. Pham, T. A. N. et al. Epithelial IL-22RA1-mediated fucosylation promotes intestinal colonization resistance to an opportunistic pathogen. Cell Host Microbe 16, 504–516 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282 (2008).

    CAS  PubMed  Google Scholar 

  25. Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

    CAS  PubMed  Google Scholar 

  26. Aparicio-Domingo, P. et al. Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage. J. Exp. Med. 212, 1783–1791 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–152 (2012).

    CAS  Google Scholar 

  29. Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mao, K. et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 554, 255–259 (2018).

    CAS  PubMed  Google Scholar 

  31. Godinho-Silva, C. et al. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature 574, 254–258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Teng, F. et al. A circadian clock is essential for homeostasis of group 3 innate lymphoid cells in the gut. Sci. Immunol. 4, eaax1215 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, Q. et al. Circadian rhythm-dependent and circadian rhythm-independent impacts of the molecular clock on type 3 innate lymphoid cells. Sci. Immunol. 4, eaay7501 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Seillet, C. et al. The neuropeptide VIP confers anticipatory mucosal immunity by regulating ILC3 activity. Nat. Immunol. 21, 168–177 (2020).

    CAS  PubMed  Google Scholar 

  35. Arjona, A. & Sarkar, D. K. Circadian oscillations of clock genes, cytolytic factors, and cytokines in rat NK cells. J. Immunol. 174, 7618–7624 (2005).

    CAS  PubMed  Google Scholar 

  36. Logan, R. W., Wynne, O., Levitt, D., Price, D. & Sarkar, D. K. Altered circadian expression of cytokines and cytolytic factors in splenic natural killer cells of Per1–/– mutant mice. J. Interf. Cytokine Res. 33, 108–114 (2013).

    CAS  Google Scholar 

  37. Manoogian, E. N. C. & Panda, S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res. Rev. 39, 59–67 (2017).

    PubMed  Google Scholar 

  38. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes. Dev. 14, 2950–2961 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Aton, S. J., Colwell, C. S., Harmar, A. J., Waschek, J. & Herzog, E. D. Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat. Neurosci. 8, 476–483 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Talbot, J. et al. Feeding-dependent VIP neuron–ILC3 circuit regulates the intestinal barrier. Nature 579, 575–580 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Iwasaki, M., Akiba, Y. & Kaunitz, J. D. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Res. 8, 1–13 (2019).

    Google Scholar 

  42. Nussbaum, J. C. et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502, 245–248 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Thaiss, C. A. et al. Microbiota diurnal rhythmicity programs host transcriptome oscillations. Cell 167, 1495–1510.e12 (2016).

    CAS  PubMed  Google Scholar 

  44. Wang, Y. et al. The intestinal microbiota regulates body composition through NFIL 3 and the circadian clock. Science 357, 912–916 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kuang, Z. et al. The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3. Science 365, 1428–1434 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Savage, A. K., Liang, H.-E. & Locksley, R. M. The development of steady-state activation hubs between adult LTi ILC3s and primed macrophages in small intestine. J. Immunol. 199, 1912–1922 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. He, W. et al. Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues. Immunity 49, 1175–1190.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Woldt, E. et al. Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat. Med. 19, 1039–1046 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sengupta, S. et al. The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress. Free. Radic. Biol. Med. 93, 177–189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Duez, H. et al. Regulation of bile acid synthesis by the nuclear receptor Rev-erbα. Gastroenterology 135, 689–698 (2008).

    CAS  PubMed  Google Scholar 

  52. Le Martelot, G. et al. REV-ERBα participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol. 7, 1–12 (2009).

    Google Scholar 

  53. Sitaula, S., Zhang, J., Ruiz, F. & Burris, T. P. Rev-erb regulation of cholesterologenesis. Biochem. Pharmacol. 131, 68–77 (2017).

    CAS  PubMed  Google Scholar 

  54. Santori, F. R. et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 21, 286–298 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Soroosh, P. et al. Oxysterols are agonist ligands of RORγt and drive TH17 cell differentiation. Proc. Natl Acad. Sci. USA 111, 12163–12168 (2014).

    CAS  PubMed  Google Scholar 

  56. Saleh, M. M. et al. Colitis-induced TH17 cells increase the risk for severe subsequent Clostridium difficile infection. Cell Host Microbe 25, 756–765.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nakagawa, T. et al. Endogenous IL-17 as a factor determining the severity of Clostridium difficile infection in mice. J. Med. Microbiol. 65, 821–827 (2016).

    CAS  PubMed  Google Scholar 

  58. Yu, H. et al. Cytokines are markers of the Clostridium difficile-induced inflammatory response and predict disease severity. Clin. Vaccine Immunol. 24, 1–11 (2017).

    Google Scholar 

  59. Balsalobre, A. et al. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science 289, 2344–2347 (2000).

    CAS  PubMed  Google Scholar 

  60. Seshadri, S., Pope, R. L. & Zenewicz, L. A. Glucocorticoids inhibit group 3 innate lymphocyte IL-22 production. J. Immunol. 201, 1267–1274 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kohsaka, A. et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab. 6, 414–421 (2007).

    CAS  PubMed  Google Scholar 

  62. Mendoza, J., Pévet, P. & Challet, E. High-fat feeding alters the clock synchronization to light. J. Physiol. 586, 5901–5910 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kim, H. Y. et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat. Med. 20, 54–61 (2014).

    CAS  PubMed  Google Scholar 

  64. Sasaki, T. et al. Innate lymphoid cells in the induction of obesity. Cell Rep. 28, 202–217.e7 (2019).

    CAS  PubMed  Google Scholar 

  65. Huang, Y. et al. IL-25-responsive, lineage-negative KLRG1hi cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat. Immunol. 16, 161–169 (2015).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank S. Gilfillan and B. Bhattarai for helpful feedback. This work was supported by National Institutes of Health (NIH) grants AI095542, DE025884, AI134236 and AI134035 (to M.C.) and T32 GM007200 (to Q.W.). M.C. receives research support from Pfizer, Crohn’s & Colitis Foundation and an anonymous donor in New York.

Author information

Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Qianli Wang & Marco Colonna

Authors
  1. Qianli Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Colonna
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Marco Colonna.

Ethics declarations

Competing interests

M.C. receives research support from Pfizer. Q.W. declares no competing interests.

Additional information

Peer review information

Nature Reviews Immunology thanks C. Scheiermann, H. Spits and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Entrainment

Synchronization of the endogenous clock to the period of an external oscillation (zeitgeber).

Phase advance

A shift in the organism’s circadian rhythm such that it starts earlier. For the studies reviewed here, this is achieved through advance in the light schedule or earlier onset of light.

Suprachiasmatic nucleus

(SCN). A group of neurons in the ventral hypothalamus that serve as the circadian pacemaker.

Zeitgebers

(Literally, ‘timegivers’). Any external time cues capable of entraining an organism.

Zeitgeber time

(ZT). A unit of time defined with reference to entraining environmental cues. In many cases, the zeitgeber time is designated in reference to light, with ZT0 denoting onset of light and ZT12 denoting onset of darkness.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Q., Colonna, M. Keeping time in group 3 innate lymphoid cells. Nat Rev Immunol 20, 720–726 (2020). https://doi.org/10.1038/s41577-020-0397-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-020-0397-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing