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Clocking in to immunity

Abstract

Circadian rhythms are a ubiquitous feature of virtually all living organisms, regulating a wide diversity of physiological systems. It has long been established that the circadian clockwork plays a key role in innate immune responses, and recent studies reveal that several aspects of adaptive immunity are also under circadian control. We discuss the latest insights into the genetic and biochemical mechanisms linking immunity to the core circadian clock of the cell and hypothesize as to why the immune system is so tightly controlled by circadian oscillations. Finally, we consider implications for human health, including vaccination strategies and the emerging field of chrono-immunotherapy.

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Fig. 1: Operation and disruption of the molecular clock in immune cells.
Fig. 2: Regulation of innate immunity in the macrophage and the lung.
Fig. 3: Regulation of adaptive immunity in the lymph node.
Fig. 4: Interactions of the clock, microbiome and immune function.
Fig. 5: Chronotherapy and the clock as a therapeutic target.

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Acknowledgements

The authors thank V. Lavilla for creating the video and M. F. Loudon for providing the voice-over to it. C.S. is funded by the German Research Foundation (DFG) (Emmy-Noether grant (SCHE 1645/2-1) and SFB914 projects B09 and Z03), the European Research Council (ERC; starting grant 635872, CIRCODE), the DZHK (German Centre for Cardiovascular Research) and the BMBF (German Ministry of Education and Research). J.G. is an Arthritis Research UK Career Development Fellow (Ref. 20629). A.L. acknowledges the support of the Wellcome Trust (grant 107851/Z/15/Z).

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Correspondence to Christoph Scheiermann or Andrew Loudon.

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Manchester Biological Timing: https://www.bmh.manchester.ac.uk/research/biological-timing/

Loudon Laboratory: http://www.manchester.ac.uk/research/Andrew.loudon/personaldetails

Scheiermann Laboratory: http://scheiermannlab.de/

Gibbs Laboratory: https://www.research.manchester.ac.uk/portal/Julie.Gibbs.html

Supplementary information

41577_2018_8_MOESM1_ESM.mp4

Movie 1: Rhythmic leukocyte activity throughout the body. Migration of leukocytes from blood to tissues (and back) is regulated at multiple levels by the circadian clock. In mice, blood leukocyte content is high during the day (rest phase) and lower at night (active phase). The factors, which generate these oscillations vary between cells and tissues. For example, neutrophils in the blood express higher levels of the chemokine receptor CXCR4 during the late day. This receptor drives neutrophil homing to bone marrow, which is therefore elevated at this time point. During the night, CXCR4 expression is reduced and less homing occurs to this organ. In the lung, resident stromal cells rhythmically produce the neutrophil chemoattractant CXCL5. Inflammatory challenge by lipopolysaccharide (LPS) inhalation during the day stimulates greater production of CXCL5 than challenge at night. The differential production of chemoattractant, along with greater numbers of neutrophils in blood, therefore leads to increased neutrophil influx to the lung during the day. By contrast, cells largely home to lymph nodes at night. During the day, T cell and B cell expression of the lymph node-homing receptor CCR7 is low, and few cells migrate into the lymph node. In addition, expression of S1PR1, the receptor which mediates lymphocyte egress, is high and cells are more prone to leave the lymph node during the day. At night, the inverse occurs and T cells and B cells are retained in the lymph node for longer. Differentiation of cells is also regulated by time-of-day, as in the case of TH17 cell development in the gut. During the day, levels of the differentiation factor RORγt are high and increased differentiation is observed relative to the dark phase. At night, RORγt activity is repressed by NFIL3 and so the differentiation stimulus is reduced. In this way, the body is primed to respond differently to inflammatory challenge at different times of day, and disruption to the circadian rhythm can have severe consequences for immune function

Glossary

Circadian

A free-running rhythm with a period of approximately 24 h that persists in the absence of external entrainment, such as in constant darkness.

Suprachiasmatic nuclei

(SCN). A bilateral structure in the anterior hypothalamus, home to the central pacemaker, which processes light input and conveys timing information to the rest of the body.

Diurnal

A pattern that occurs over the course of a day in which external entrainment (such as light–dark cycles) is used; the onset of the light cycle is defined as Zeitgeber time 0 (ZT0).

Period circadian protein homologue 1

(PER1). PER1, PER2 and PER3 are PAS (PER–ARNT–SIM) domain-containing proteins that associate with CRY proteins to inhibit BMAL1–CLOCK-mediated gene expression.

REV-ERB

REV-ERBα (encoded by NR1D1) and REV-ERBβ (encoded by NR1D2) are transcriptional repressors that bind to ROR response element (RORE) motifs in the BMAL1 promoter to regulate the rhythmic expression of BMAL1.

Cryptochromes

(CRYs). CRY1 and CRY2 are transcriptional repressors that associate with PER proteins to inhibit BMAL1–CLOCK-mediated gene transcription.

Brain and muscle ARNT-like 1

(BMAL1). A basic helix–loop–helix PER–ARNT–SIM (bHLH–PAS) domain transcription factor that dimerizes with CLOCK to bind E-boxes in gene promoters to induce circadian gene expression.

CLOCK

(Circadian locomoter output cycles kaput). A basic helix–loop–helix PER–ARNT–SIM (bHLH–PAS) domain transcription factor that can dimerize with BMAL1 to regulate circadian gene expression.

Zeitgeber time

Zeitgeber, literally ‘time giver’, is a cue (such as light) that entrains the circadian clock. Zeitgeber time (ZT) is the time after light onset; for example, lights on is ZT0 and lights off is ZT12 in a 12 h light-12 h dark cycle.

Circadian time

(CT). A measure of subjective time used when organisms are isolated from Zeitgebers (for example, constant darkness). CT0 represents the start of subjective day and CT12 represents the start of subjective night.

RORα

The nuclear receptors RORα, RORβ and RORγ are transcriptional activators that bind to ROR response element (RORE) sites in target gene promoters.

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Scheiermann, C., Gibbs, J., Ince, L. et al. Clocking in to immunity. Nat Rev Immunol 18, 423–437 (2018). https://doi.org/10.1038/s41577-018-0008-4

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