TH17 cell differentiation is regulated by the circadian clock

Science. 2013 Nov 8;342(6159):727-30. doi: 10.1126/science.1243884.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CLOCK Proteins / genetics
  • Cell Differentiation / genetics*
  • Cell Lineage / genetics
  • Circadian Clocks / genetics
  • Circadian Clocks / immunology*
  • Gene Expression Regulation*
  • Germ-Free Life
  • HEK293 Cells
  • Humans
  • Intestine, Small / immunology
  • Intestine, Small / microbiology
  • Jurkat Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Promoter Regions, Genetic
  • Th17 Cells / cytology*


  • Basic-Leucine Zipper Transcription Factors
  • Nfil3 protein, mouse
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rorc protein, mouse
  • CLOCK Proteins
  • Clock protein, mouse