Editors' ChoiceImmunology

For Whom the Clock Tolls

Science Signaling  28 Feb 2012:
Vol. 5, Issue 213, pp. ec66
DOI: 10.1126/scisignal.2003001

Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs) and stimulate the innate and adaptive immune responses. TLR9 responds to microbial DNA containing CpG dinucleotides, leading to production of type I interferons and inflammatory cytokines (see commentary by Obermann and Bauer). Noting that circadian rhythms regulate aspects of immunity such as lymphocyte proliferation and cytokine production, Silver et al. investigated whether the innate immune response to pathogens was also under circadian control. Macrophages from Per2 mutant mice (which have a defective circadian molecular clock) produced fewer cytokines than did macrophages from wild-type mice in response to the TLR9 ligand CpG oligodeoxynucleotide (ODN); however, other TLR responses were unaffected. Mice were exposed to a 12-hour light and 12-hour dark cycle starting at Zeitgeber time (ZT) 0, and messenger RNA (mRNA) abundance in the spleen was measured every 4 hours. Whereas Tlr9 mRNA abundance peaked at ZT 19, the mRNAs for other TLRs did not change. TLR9 protein abundance in the spleen also showed circadian regulation, being higher at ZT19 than at ZT7. Mice exposed to CpG ODNs at ZT19 produced greater amounts of mRNAs for inflammatory cytokines than did mice exposed at ZT7, although there were no differences in baseline amounts of mRNAs. Mice injected at ZT19 with antigenic peptide and CpG ODNs (as a vaccine adjuvant) showed enhanced antigen responsiveness 4 weeks after vaccination compared with mice vaccinated at ZT7. Finally, in a mouse model of TLR9-dependent sepsis, cecal ligation and puncture resulted in a worse phenotype in mice that underwent the procedure at ZT19 than in mice treated at ZT7, indicating a correlation between TLR9 abundance and disease severity. Together, these data suggest a link between the circadian system and innate immunity that may have implications for immunotherapy.

A. C. Silver, A. Arjona, W. E. Walker, E. Fikrig, The circadian clock controls Toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36, 251–261 (2012). [PubMed]

H.-L. Obermann, S. Bauer, Toll-like receptor 9, what o’clock is it? Immunity 36, 159–161 (2012). [Abstract]