Circadian Rhythms in Immunity


Purpose of Review

This review is focused on the existing evidence for circadian control of innate and adaptive immune responses to provide a framework for evaluating the contributions of diurnal rhythms to control of infections and pathogenesis of disease.

Recent Findings

Circadian rhythms driven by cell-autonomous biological clocks are central to innate and adaptive immune responses against microbial pathogens. Research during the past few years has uncovered circadian circuits governing leukocyte migration between tissues, the magnitude of mucosal inflammation, the types of cytokines produced, and the severity of immune diseases. Other studies revealed how disruption of the circadian clock impairs immune function or how microbial products alter clock machinery.


Revelations concerning the widespread impact of the circadian clock on immunity and homeostasis highlight how the timing of inflammatory challenges can dictate pathological outcomes and how the timing of therapeutic interventions likely determines clinical efficacy. An improved understanding of circadian circuits controlling immune function will facilitate advances in circadian immunotherapy.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Turek FW. Circadian clocks: not your grandfather’s clock. Science. 2016;354(6315):992–3.

  2. 2.

    Man K, Loudon A, Chawla A. Immunity around the clock. Science. 2016;354(6315):999–1003.

  3. 3.

    • Scheiermann C, et al. Clocking in to immunity. Nat Rev Immunol. 2018;18(7):423–37 Outstanding comprehensive review of circadian aspects of immunity.

  4. 4.

    Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018;19(8):453–69.

  5. 5.

    Cheng MY, Bullock CM, Li C, Lee AG, Bermak JC, Belluzzi J, et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature. 2002;417(6887):405–10.

  6. 6.

    Brancaccio M, et al. Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science. 2019;363(6423):187–92.

  7. 7.

    Burki T. Nobel Prize awarded for discoveries in circadian rhythm. Lancet. 2017;390(10104):e25.

  8. 8.

    Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164–79.

  9. 9.

    Young MW, Kay SA. Time zones: a comparative genetics of circadian clocks. Nat Rev Genet. 2001;2(9):702–15.

  10. 10.

    Allada R, Emery P, Takahashi JS, Rosbash M. Stopping time: the genetics of fly and mouse circadian clocks. Annu Rev Neurosci. 2001;24:1091–119.

  11. 11.

    Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, et al. The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell. 2002;110(2):251–60.

  12. 12.

    Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron. 2004;43(4):527–37.

  13. 13.

    Mitsui S, Yamaguchi S, Matsuo T, Ishida Y, Okamura H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev. 2001;15(8):995–1006.

  14. 14.

    Kostrzewski T, et al. Multiple levels of control determine how E4bp4/Nfil3 regulates NK cell development. J Immunol. 2018;200(4):1370–81.

  15. 15.

    Geiger TL, Abt MC, Gasteiger G, Firth MA, O'Connor MH, Geary CD, et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med. 2014;211(9):1723–31.

  16. 16.

    Seillet C, Rankin LC, Groom JR, Mielke LA, Tellier J, Chopin M, et al. Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med. 2014;211(9):1733–40.

  17. 17.

    Male V, Nisoli I, Kostrzewski T, Allan DS, Carlyle JR, Lord GM, et al. The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression. J Exp Med. 2014;211(4):635–42.

  18. 18.

    Kamizono S, Duncan GS, Seidel MG, Morimoto A, Hamada K, Grosveld G, et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J Exp Med. 2009;206(13):2977–86.

  19. 19.

    Xu W, Domingues RG, Fonseca-Pereira D, Ferreira M, Ribeiro H, Lopez-Lastra S, et al. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep. 2015;10(12):2043–54.

  20. 20.

    Yu X, et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. Elife. 2014;3:e04406.

  21. 21.

    Sun Y, Yang Z, Niu Z, Peng J, Li Q, Xiong W, et al. MOP3, a component of the molecular clock, regulates the development of B cells. Immunology. 2006;119(4):451–60.

  22. 22.

    Hemmers S, Rudensky AY. The cell-intrinsic circadian clock is dispensable for lymphocyte differentiation and function. Cell Rep. 2015;11(9):1339–49.

  23. 23.

    Yu X, Rollins D, Ruhn KA, Stubblefield JJ, Green CB, Kashiwada M, et al. TH17 cell differentiation is regulated by the circadian clock. Science. 2013;342(6159):727–30.

  24. 24.

    Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28(1):29–39.

  25. 25.

    Nguyen KD, Fentress SJ, Qiu Y, Yun K, Cox JS, Chawla A. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science. 2013;341(6153):1483–8.

  26. 26.

    Casanova-Acebes M, Pitaval C, Weiss LA, Nombela-Arrieta C, Chèvre R, A-González N, et al. Rhythmic modulation of the hematopoietic niche through neutrophil clearance. Cell. 2013;153(5):1025–35.

  27. 27.

    Mendez-Ferrer S, et al. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452(7186):442–7.

  28. 28.

    Haspel JA, et al. Circadian rhythm reprogramming during lung inflammation. Nat Commun. 2014;5:4753.

  29. 29.

    Gibbs J, Ince L, Matthews L, Mei J, Bell T, Yang N, et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med. 2014;20(8):919–26.

  30. 30.

    • Shimba A, et al. Glucocorticoids Drive Diurnal Oscillations in T Cell Distribution and Responses by Inducing Interleukin-7 Receptor and CXCR4. Immunity. 2018;48(2):286–298 e6 This study reveals how circadian oscillations in glucocorticoids influence T cell survival and tissue distribution.

  31. 31.

    •• He W, et al. Circadian Expression of Migratory Factors Establishes Lineage-Specific Signatures that Guide the Homing of Leukocyte Subsets to Tissues. Immunity. 2018;49(6):1175–1190 e7 A powerful circadian screen of adhesion and migratory receptors on leukocytes and endothelial cells reveals mechanisms driving time-of-day changes in leukocytes frequencies in various tissues.

  32. 32.

    • Druzd D, et al. Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses. Immunity. 2017;46(1):120–32 This study reveals rhythmic expression of migratory factors and associated oscillations in lymphocyte transit between blood and lymphoid tissues.

  33. 33.

    • Adrover JM, et al. A Neutrophil Timer Coordinates Immune Defense and Vascular Protection. Immunity. 2019;50(2):390–402 e10 This article identifies a cell-intrinsic clock in neutrophils dictating egress from blood to control infections and prevent vascular injury.

  34. 34.

    Christ P, et al. The circadian clock drives mast cell functions in allergic reactions. Front Immunol. 2018;9:1526.

  35. 35.

    Silver AC, Arjona A, Walker WE, Fikrig E. The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity. 2012;36(2):251–61.

  36. 36.

    Bellet MM, Deriu E, Liu JZ, Grimaldi B, Blaschitz C, Zeller M, et al. Circadian clock regulates the host response to salmonella. Proc Natl Acad Sci U S A. 2013;110(24):9897–902.

  37. 37.

    Logan RW, Wynne O, Levitt D, Price D, Sarkar DK. Altered circadian expression of cytokines and cytolytic factors in splenic natural killer cells of Per1(−/−) mutant mice. J Interf Cytokine Res. 2013;33(3):108–14.

  38. 38.

    Nussbaum JC, van Dyken S, von Moltke J, Cheng LE, Mohapatra A, Molofsky AB, et al. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013;502(7470):245–8.

  39. 39.

    Lam MT, Cho H, Lesch HP, Gosselin D, Heinz S, Tanaka-Oishi Y, et al. Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature. 2013;498(7455):511–5.

  40. 40.

    Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, et al. The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 2012;109(2):582–7.

  41. 41.

    • Allen NC, et al. Desynchronization of the molecular clock contributes to the heterogeneity of the inflammatory response. Sci Signal. 2019;12(571) This work reveals a mechanism of inflammatory heterogeneity driven by desynchronization of the molecular clock in myeloid cells.

  42. 42.

    Kiessling S, Dubeau-Laramée G, Ohm H, Labrecque N, Olivier M, Cermakian N. The circadian clock in immune cells controls the magnitude of Leishmania parasite infection. Sci Rep. 2017;7(1):10892.

  43. 43.

    Hopwood TW, Hall S, Begley N, Forman R, Brown S, Vonslow R, et al. The circadian regulator BMAL1 programmes responses to parasitic worm infection via a dendritic cell clock. Sci Rep. 2018;8(1):3782.

  44. 44.

    Early JO, Menon D, Wyse CA, Cervantes-Silva MP, Zaslona Z, Carroll RG, et al. Circadian clock protein BMAL1 regulates IL-1beta in macrophages via NRF2. Proc Natl Acad Sci U S A. 2018;115(36):E8460–8.

  45. 45.

    Majumdar T, Dhar J, Patel S, Kondratov R, Barik S. Circadian transcription factor BMAL1 regulates innate immunity against select RNA viruses. Innate Immun. 2017;23(2):147–54.

  46. 46.

    Zhuang X, Magri A, Hill M, Lai AG, Kumar A, Rambhatla SB, et al. The circadian clock components BMAL1 and REV-ERBalpha regulate flavivirus replication. Nat Commun. 2019;10(1):377.

  47. 47.

    • Ehlers A, et al. BMAL1 links the circadian clock to viral airway pathology and asthma phenotypes. Mucosal Immunol. 2018;11(1):97–111 The authors demonstrate circadian control of immune responses against respiratory pathogens that dictate severity of lung inflammation and pathogenesis of asthma-like disease.

  48. 48.

    Edgar RS, Stangherlin A, Nagy AD, Nicoll MP, Efstathiou S, O’Neill JS, et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proc Natl Acad Sci U S A. 2016;113(36):10085–90.

  49. 49.

    •• Sengupta S, et al. Circadian control of lung inflammation in influenza infection. Nat Commun. 2019;10(1):4107 Exciting study revealing that time-of-day susceptibility to morbidity and mortality during influenza infection is attributable to differences in number and function of innate lymphocytes as well as inflammatory monocytes in the lung.

  50. 50.

    Mukherji A, Kobiita A, Ye T, Chambon P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell. 2013;153(4):812–27.

  51. 51.

    • Wang Y, et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science. 2017;357(6354):912–6 This study reveals crosstalk between circadian proteins REV-ERBα and NFIL3 critical for proper regulation of Th17 differentiation and lipid metabolism.

  52. 52.

    •• Godinho-Silva C, et al. Light-entrained and brain-tuned circadian circuits regulate ILC3s and gut homeostasis. Nature. 2019;574(7777):254-258.

  53. 53.

    •• Kuang Z, et al. The intestinal microbiota programs diurnal rhythms in host metabolism through histone deacetylase 3. Science. 2019;365(6460):1428–34 The authors show that microbiota program circadian rhythms in intestinal epithelium via activation of HDAC3.

  54. 54.

    Fortier EE, et al. Circadian variation of the response of T cells to antigen. J Immunol. 2011;187(12):6291–300.

  55. 55.

    •• Sutton CE, et al. Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease. Nat Commun. 2017;8(1):1923 Crosstalk between T cells and APC is under stringent clock control to limit development of autoimmune-disease causing Th1 and Th17 cells.

  56. 56.

    • Nobis CC, et al. The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways. Proc Natl Acad Sci U S A. 2019;116:20077 Circadian rhythms in DCs determine amplitude of CD8 T cell responses after immunization.

  57. 57.

    • Suzuki K, et al. Adrenergic control of the adaptive immune response by diurnal lymphocyte recirculation through lymph nodes. J Exp Med. 2016;213(12):2567–74 Demonstration of adrenergic control of lymphocyte trafficking and resulting humoral immune responses.

  58. 58.

    Long JE, Drayson MT, Taylor AE, Toellner KM, Lord JM, Phillips AC. Corrigendum to 'Morning vaccination enhances antibody response over afternoon vaccination: a cluster-randomised trial' [vaccine 34 (2016) 2679-2685]. Vaccine. 2016;34(40):4842.

  59. 59.

    • Cao Q, et al. Circadian clock cryptochrome proteins regulate autoimmunity. Proc Natl Acad Sci U S A. 2017;114(47):12548–53 This study reveals that CRY genes are critical for prevention of exaggerated responses of autoreactive B cells like those observed in human lupus.

  60. 60.

    Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3(5):350–61.

  61. 61.

    Masri S, Papagiannakopoulos T, Kinouchi K, Liu Y, Cervantes M, Baldi P, et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell. 2016;165(4):896–909.

  62. 62.

    • Sulli G, et al. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. Nature. 2018;553(7688):351–5 Agonism of REV-ERBs is lethal to cancer cells via inhibition of autophagy and lipid metabolism.

  63. 63.

    Deng W, Zhu S, Zeng L, Liu J, Kang R, Yang M, et al. The circadian clock controls immune checkpoint pathway in sepsis. Cell Rep. 2018;24(2):366–78.

  64. 64.

    • Nakao A. Clockwork allergy: How the circadian clock underpins allergic reactions. J Allergy Clin Immunol. 2018;142(4):1021–31 Comprehensive review of the intersections between circadian biology and clinical presentation of allergic and asthmatic diseases.

  65. 65.

    Zaslona Z, et al. The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma. Am J Physiol Lung Cell Mol Physiol. 2017;312(6):L855–60.

  66. 66.

    • Kawauchi T, et al. Clock-dependent temporal regulation of IL-33/ST2-mediated mast cell response. Allergol Int. 2017;66(3):472–8 This study shows that CLOCK regulates IL-33-mast cell axis via constraint of cytokines and cytokine receptor expression.

  67. 67.

    Cederroth CR, Albrecht U, Bass J, Brown SA, Dyhrfjeld-Johnsen J, Gachon F, et al. Medicine in the fourth dimension. Cell Metab. 2019;30(2):238–50.

  68. 68.

    Sitaula S, Billon C, Kamenecka TM, Solt LA, Burris TP. Suppression of atherosclerosis by synthetic REV-ERB agonist. Biochem Biophys Res Commun. 2015;460(3):566–71.

  69. 69.

    Hand LE, Hopwood TW, Dickson SH, Walker AL, Loudon AS, Ray DW, et al. The circadian clock regulates inflammatory arthritis. FASEB J. 2016;30(11):3759–70.

  70. 70.

    Scheiermann C, Kunisaki Y, Lucas D, Chow A, Jang JE, Zhang D, et al. Adrenergic nerves govern circadian leukocyte recruitment to tissues. Immunity. 2012;37(2):290–301.

  71. 71.

    Borniger JC, et al. Time-of-day dictates transcriptional inflammatory responses to cytotoxic chemotherapy. Sci Rep. 2017;7:41220.

Download references


I wish to thank Lauren Francey and John Hogenesch for reading the manuscript and providing helpful feedback.

Funding Information

The author is supported by the National Institutes of Health (NIH) grants DA038017, AI148080, and AR073228, as well as by the Cincinnati Children’s Research Foundation.

Author information

Correspondence to Stephen N. Waggoner.

Ethics declarations

Conflict of Interest

The author declares no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

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

This article is part of the Topical Collection on Basic and Applied Science

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Waggoner, S.N. Circadian Rhythms in Immunity. Curr Allergy Asthma Rep 20, 2 (2020).

Download citation


  • Clock
  • Migration
  • Allergy
  • Asthma
  • Microbiota
  • Infection