The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity

Immunity. 2012 Feb 24;36(2):251-61. doi: 10.1016/j.immuni.2011.12.017.


Circadian rhythms refer to biologic processes that oscillate with a period of ~24 hr. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of Toll-like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Circadian Clocks / genetics
  • Circadian Clocks / immunology*
  • Cytokines / biosynthesis
  • Gene Expression
  • Immunity, Innate*
  • Immunization
  • Macrophages, Peritoneal / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / immunology
  • Promoter Regions, Genetic
  • Sepsis / genetics
  • Sepsis / immunology
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / immunology*


  • Cytokines
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9