Hooper and colleagues show that the transcription factor NFIL3 integrates signals from the circadian clock to regulate T helper 17 (TH17) cell development in mice. NFIL3 suppressed TH17 cell development by repressing Rorc (which encodes RORγt) transcription, and NFIL3 itself was suppressed by the clock regulator REV-ERBα. Nfil3 and Rorc were expressed in opposite phases of the circadian cycle, with Nfil3 expression lower during the day (a 12-hour light cycle) and higher at night (a 12-hour dark cycle). Accordingly, CD4+ T cells isolated from mice during the day showed a higher propensity for differentiating into TH17 cells following in vitro polarization. Notably, mice exposed to chronic light-cycle perturbations had increased frequencies of TH17 cells in the spleen and small intestine, and were more susceptible to chemically induced colitis than mice maintained under a normal light cycle. Interestingly, Nfil3 polymorphisms, night-shift work and jet lag are all linked to human inflammatory diseases — the authors suggest that this could be due to the disruption of circadian pathways that regulate pro-inflammatory immune responses.
References
Yu, X. et al. TH17 cell differentiation is regulated by the circadian clock. Science http://dx.doi.org/10.1126/science.1243884 (2013)
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Bordon, Y. NFIL3 clocks out TH17 cells. Nat Rev Immunol 13, 848 (2013). https://doi.org/10.1038/nri3574
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DOI: https://doi.org/10.1038/nri3574