TH17 Cell Differentiation Is Regulated by the Circadian Clock

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 ROR gamma t. We show that the transcription factor NFIL3 suppresses T(H)17 cell development by directly binding and repressing the Ror gamma t promoter. NFIL3 links T(H)17 cell development to the circadian clock network through the transcription factor REV-ERB alpha. Accordingly, T(H)17 lineage specification varies diurnally and is altered in Rev-erba(-/-) 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.