TH17 Cell Differentiation is Regulated by the Circadian Clock

Overview

Journal Science

Specialty Science

Date 2013 Nov 9

PMID 24202171

Citations 206

Authors

Xiaofei Yu

Darcy Rollins

Kelly A Ruhn

Jeremy J Stubblefield

Carla B Green

Masaki Kashiwada

Paul B Rothman

Joseph S Takahashi

Lora V Hooper

Affiliations

Soon will be listed here.

Abstract

Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. Interleukin-17-producing CD4(+) T helper (T(H)17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORγt. We show that the transcription factor NFIL3 suppresses T(H)17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links T(H)17 cell development to the circadian clock network through the transcription factor REV-ERBα. Accordingly, TH17 lineage specification varies diurnally and is altered in Rev-erbα(-/-) mice. Light-cycle disruption elevated intestinal T(H)17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.

Citing Articles

Personalization of Cancer Treatment: Exploring the Role of Chronotherapy in Immune Checkpoint Inhibitor Efficacy.

Fey R, Billo A, Clister T, Doan K, Berry E, Tibbitts D Cancers (Basel). 2025; 17(5).

PMID: 40075580 PMC: 11899640. DOI: 10.3390/cancers17050732.

Epigenetic Mechanisms in the Transcriptional Regulation of Circadian Rhythm in Mammals.

Mao W, Ge X, Chen Q, Li J Biology (Basel). 2025; 14(1.

PMID: 39857273 PMC: 11762092. DOI: 10.3390/biology14010042.

Circadian metabolic adaptations to infections.

Costantini C, Brancorsini S, Grignani F, Romani L, Bellet M Philos Trans R Soc Lond B Biol Sci. 2025; 380(1918):20230473.

PMID: 39842481 PMC: 11753887. DOI: 10.1098/rstb.2023.0473.

Circadian Rhythm Disruption Exacerbates Autoimmune Uveitis: The Essential Role of PER1 in Treg Cell Metabolic Support for Stability and Function.

Zhu W, Chen G, Xiao Z, Wang M, Li Z, Shi Y Adv Sci (Weinh). 2025; 12(10):e2400004.

PMID: 39823532 PMC: 11904989. DOI: 10.1002/advs.202400004.

Psoriasis and Seasonality: Exploring the Genetic and Epigenetic Interactions.

Niedzwiedz M, Skibinska M, Ciazynska M, Noweta M, Czerwinska A, Krzyscin J Int J Mol Sci. 2024; 25(21).

PMID: 39519223 PMC: 11547062. DOI: 10.3390/ijms252111670.

References

Hu W, Troutman T, Edukulla R, Pasare C . Priming microenvironments dictate cytokine requirements for T helper 17 cell lineage commitment. Immunity. 2011; 35(6):1010-22. PMC: 3246047. DOI: 10.1016/j.immuni.2011.10.013. View

Huh J, Wu J, Lee C, Yun M, Gilada D, Brautigam C . Multivalent di-nucleosome recognition enables the Rpd3S histone deacetylase complex to tolerate decreased H3K36 methylation levels. EMBO J. 2012; 31(17):3564-74. PMC: 3433781. DOI: 10.1038/emboj.2012.221. View

King D, Zhao Y, Sangoram A, Wilsbacher L, Tanaka M, Antoch M . Positional cloning of the mouse circadian clock gene. Cell. 1997; 89(4):641-53. PMC: 3815553. DOI: 10.1016/s0092-8674(00)80245-7. View

Motomura Y, Kitamura H, Hijikata A, Matsunaga Y, Matsumoto K, Inoue H . The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nat Immunol. 2011; 12(5):450-9. PMC: 3494493. DOI: 10.1038/ni.2020. View

Bollinger T, Leutz A, Leliavski A, Skrum L, Kovac J, Bonacina L . Circadian clocks in mouse and human CD4+ T cells. PLoS One. 2012; 6(12):e29801. PMC: 3247291. DOI: 10.1371/journal.pone.0029801. View

Maloy K, Kullberg M . IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 2008; 1(5):339-49. DOI: 10.1038/mi.2008.28. View

Kiss E, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C . Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 2011; 334(6062):1561-5. DOI: 10.1126/science.1214914. View

Kouzine F, Wojtowicz D, Yamane A, Resch W, Kieffer-Kwon K, Bandle R . Global regulation of promoter melting in naive lymphocytes. Cell. 2013; 153(5):988-99. PMC: 3684982. DOI: 10.1016/j.cell.2013.04.033. View

Scheer F, Hilton M, Mantzoros C, Shea S . Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009; 106(11):4453-8. PMC: 2657421. DOI: 10.1073/pnas.0808180106. View

10.

Pepper M, Linehan J, Pagan A, Zell T, Dileepan T, Cleary P . Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat Immunol. 2009; 11(1):83-9. PMC: 2795784. DOI: 10.1038/ni.1826. View

11.

Vitaterna M, King D, Chang A, Kornhauser J, Lowrey P, McDonald J . Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science. 1994; 264(5159):719-25. PMC: 3839659. DOI: 10.1126/science.8171325. View

12.

Ivanov I, McKenzie B, Zhou L, Tadokoro C, Lepelley A, Lafaille J . The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126(6):1121-33. DOI: 10.1016/j.cell.2006.07.035. View

13.

Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F . A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2):289-303. PMC: 3503487. DOI: 10.1016/j.cell.2012.09.016. View

14.

Jostins L, Ripke S, Weersma R, Duerr R, McGovern D, Hui K . Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012; 491(7422):119-24. PMC: 3491803. DOI: 10.1038/nature11582. View

15.

Hooper L, Macpherson A . Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. 2010; 10(3):159-69. DOI: 10.1038/nri2710. View

16.

Ivanov I, de Llanos Frutos R, Manel N, Yoshinaga K, Rifkin D, Sartor R . Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008; 4(4):337-49. PMC: 2597589. DOI: 10.1016/j.chom.2008.09.009. View

17.

Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U . The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002; 110(2):251-60. DOI: 10.1016/s0092-8674(02)00825-5. View

18.

Duez H, van der Veen J, Duhem C, Pourcet B, Touvier T, Fontaine C . Regulation of bile acid synthesis by the nuclear receptor Rev-erbalpha. Gastroenterology. 2008; 135(2):689-98. DOI: 10.1053/j.gastro.2008.05.035. View

19.

Koike N, Yoo S, Huang H, Kumar V, Lee C, Kim T . Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012; 338(6105):349-54. PMC: 3694775. DOI: 10.1126/science.1226339. View

20.

Bechtold D, Gibbs J, Loudon A . Circadian dysfunction in disease. Trends Pharmacol Sci. 2010; 31(5):191-8. DOI: 10.1016/j.tips.2010.01.002. View