CLOCK is an Epigenetic Integrator of Circadian Rhythm and T Cell Immunity

Apr 3, 2026Research square

CLOCK protein links daily body rhythms with T cell immune responses

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

The mutant CLOCKΔ19 disrupts circadian transcription and globally reduces chromatin accessibility.

CLOCK and BMAL1 interact to regulate both circadian rhythms and metabolic processes in T cells.
CLOCK binding at promoters and CLOCK-BMAL1 binding at enhancers influence immune-related gene expression.
Disruption of circadian regulation leads to increased Th17 cell responses and reduced production of IFN-γ during viral infections.
Mutant CLOCKΔ19 is associated with enhanced expansion of RORγt⁺ CD4⁺ T cells and regulatory T cells.
Loss of normal CLOCK function may impair the regulatory role of Treg cells on Th17 responses.

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The circadian clock imposes a critical yet incompletely understood layer of regulation on adaptive immunity. T helper 17 (Th17) antimicrobial immune responses including expression of IL-17A by lamina propria CD4⁺ T cells, exhibit diurnal variation and are sensitive to circadian disruption. While the core circadian regulators CLOCK and BMAL1 canonically function as a heterodimer to drive rhythmic gene expression, emerging evidence suggests they may have distinct regulatory roles. Here we integrated ChIP-seq, ATAC-seq, and RNA-seq analyses in naïve CD4⁺ T cells to reveal that the CLOCK-BMAL1 complex controls circadian and metabolic programs through promoter binding, whereas exclusive CLOCK binding at promoters, together with CLOCK-BMAL1 binding at enhancers, regulates immune-associated genes. Using the mutant CLOCKΔ19, which lacks the transactivation domain, we observed disrupted circadian transcription and globally reduced chromatin accessibility, alongside increased accessibility at Th17-associated loci that their altered temporal regulation. Functionally, ClockΔ19 produces β-catenin stabilization in T cells, pronounced expansion of RORγt⁺ CD4⁺ T cells and Treg cells, impaired Treg suppression of Th17 responses, heightened Th17 responses, and reduced IFN-γ production during viral infection. Collectively, these findings define BMAL1 dependent and independent CLOCK functions that program naïve CD4⁺ T cell fate, restrain Th17 differentiation, and preserve immune homeostasis.