Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt

The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a –2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation. Colonna and colleagues show that the clock genes encoding REV-ERBα and REV-ERBβ maintain ILC3 functions in the gut by controlling the expression of RORγt.