Biochemical and Biophysical Research Communications
The frequency of Th17 cells in the small intestine exhibits a day–night variation dependent on circadian clock activity
Graphical abstract
Introduction
Interleukin-17–producing CD4+ T helper (Th17) cells are a lineage of CD4+ T cells that play critical roles in bacterial and fungal infections at mucosal surfaces, as well as autoimmunity, by expressing the cytokines IL-17A, IL-17F, and IL-22 [1]. Their lineage specification is regulated by the orphan nuclear receptor RORγt (encoded by the RORc gene) [2]. A unique feature of Th17 cells at steady state is their ubiquitous presence in the lamina propria (LP) of the small intestine [1].
The Th17 cell population in the LP of the small intestine at steady state is regulated by several mechanisms, reflecting the importance of maintaining the numbers of these cells in the correct balance. For instance, the number of small intestine LP Th17 cells is dramatically reduced in germ-free mice, suggesting that the presence of the microbiota is required for the induction of steady-state Th17 cells in the small intestine [3]. This can be attributed to microbiota-induced IL-1β, which acts directly on IL-1 receptor (IL-1R)-expressing T cells and drives the generation of small intestine LP Th17 cells [4].
Organisms living on Earth, which rotates with a period of 24 h, have evolved timing mechanisms called “circadian clocks” to coordinate their physiology and behavior to specific times of the day [5], [6]. In mammals, the central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. This central pacemaker integrates light cues and synchronizes peripheral oscillators (peripheral clocks) present in virtually all cell types, including T cells, via neural and endocrine pathways, thereby acting as a timekeeper throughout the entire body [5], [6]. At the molecular level, the circadian clock consists of interlocked transcriptional–translational feedback loops (TTFLs), which operate in a cell-autonomous manner; both the central and peripheral clocks are conserved. Briefly, the transcription factors BMAL1 and CLOCK form the core of the central oscillatory loop. The BMAL1:CLOCK heterodimer binds E-box sites and drives expression of its own repressors Period (Per1-3), Cryptochrome (Cry1-2), and Rev-Erb (α, β), thereby generating ∼24-h oscillations in the expression of these genes in individual cells [5], [6].
Increasing evidence suggest that the circadian and immune systems are engaged in intimate interactions [7], [8]. However, it remains unclear whether the ubiquitous presence of Th17 cells in the LP of the small intestine at steady state is under the influence of circadian clock activity. This study investigated whether the circadian clock regulates the proportion of Th17 cells in the small intestine at steady state, using Clock-mutated mice [9] and mice housed under aberrant light conditions.
Section snippets
Mice
Female 6-week-old C57BL6/J mice (Japan SLC) and C57BL/6 Clock Δ19/Δ19 mice were reared under conventional conditions. Clock Δ19/Δ19 mice have an A-to-T point mutation in the 5′ splice site of intron 19 and, as a consequence, an in-frame deletion of the entire exon 19 (Clock Δ19/Δ19), resulting in loss of normal transcription activity [9]. This autosomal dominant mutation eventually provokes arrhythmicity in mice. All mouse strains, if not specified otherwise, were housed under 12-h light/12-h
Results and discussion
The proportion of Th17 cells in the small intestine varies with the time of day, dependent on functional Clock activity.
Under normal conditions, in which mice were housed under 12-h light/12-h dark conditions (light/dark [LD] 12/12 cycles; the light was turned on at 6:00 a.m., Zeitgeber time [ZT] 0, and turned off at 6:00 p.m., ZT12), we found that the proportion of CD4+IL-17+ cells or CD4+Rorγt+ cells and RORc mRNA expression levels in the LP of the small intestine were significantly higher at
Grant support
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (JP15H04864).
Conflict of interest
The authors declare that they have no relevant conflicts of interest.
Acknowledgements
We thank Ms. Tomoko Tohno, Kyoko Kayama, and Mutsuko Hara for their valuable assistance.
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