Abstract

The intestine undergoes predictable diurnal oscillations in microbial burden and nutrient availability, coordinated by circadian programs that couple metabolism to immune function. Group 3 innate lymphoid cells (ILC3s), defined by RORγt expression, preserve barrier integrity through IL-22 production but retain the capacity to transdifferentiate into T-bet–dependent, IFNγ-producing type 1 innate lymphoid cells (ILC1)-like cells. Although circadian regulators have been implicated in ILC3 biology, the underlying mechanisms remain poorly defined. Here, we demonstrate that the nuclear receptors REV-ERBα and REV-ERBβ are essential for maintaining ILC3 lineage stability. Combined deletion of REV-ERBα and REV-ERBβ drives ILC3-to-ILC1 conversion, impairs cellular bioenergetics and IL-22 production, enhances IFNγ expression, and increases susceptibility to Citrobacter rodentium infection. Single-cell multiomic profiling and targeted gene perturbation reveal that REV-ERBα/β deficiency induces NFIL3, which represses RORγt expression through a −2 kb cis-regulatory element within the Rorc locus, thereby promoting a T-bet–dominated transcriptional program. Integrated chromatin and metabolic analyses further establish that loss of REV-ERBα/β remodels both regulatory and metabolic networks. Collectively, these findings identify REV-ERBα/β as critical safeguards of intestinal homeostasis that couple circadian control to RORγt-dependent ILC3 identity and function.

Committee Chair

Marco Colonna

Committee Members

Aydan Szeto; Erik Musiek; Steve Van Dyken; Wayne Yokoyama

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-21-2026

Language

English (en)

Author's ORCID

https://orcid.org/0009-0003-1263-8554

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Available for download on Thursday, April 20, 2028

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