TH17 Cell Differentiation Is Regulated by the Circadian Clock

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Science  08 Nov 2013:
Vol. 342, Issue 6159, pp. 727-730
DOI: 10.1126/science.1243884

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Lighting Up Immunity

TH17 cells are CD4+ T helper cells that produce the proinflammatory cytokine interleukin-17. In the intestines, TH17 cells protect the host from fungal and bacterial infections, and their proinflammatory function is linked with autoimmune diseases including inflammatory bowel disease. Yu et al. (p. 727) show that the molecular circadian clock directly regulates the differentiation of TH17 cells in the intestine, which suggest that both nutrition and light are important environmental factors that directly regulate the immune response.


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 (TH17) 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 TH17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links TH17 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 TH17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.

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