The circadian clock gene ARNTL regulates the expression of <i>CCR6</i> and Th17 related genes in human cells

Abstract Previously we have shown that CCR6 expression uniquely defines a major branch of the Th effector/memory population that includes cells with both Th17 and Th17-associated phenotypes, therefore, studying the regulation of CCR6 will reveal molecular mechanisms important for controlling broad aspects of the functions of Th17 and associated cell types. Microarray analysis of CD4+ memory T cells from adult blood, based on CCR6 expression, revealed that among many transcription factors which were differentially expressed in the CCR6+ vs CCR6− cells, 8 were identified as regulators of circadian rhythm including ARNTL/BMAL1, a basic-helix-loop-helix-PAS domain transcription factor that as part of a heterodimer with CLOCK/NPAS1 is a central component of the circadian clock within the brain, and functions in analogous transcriptional circuits in peripheral tissues, including cells of the immune system. We found that ARNTL was progressively up-regulated among the CCR6-expressing cells and that it has a predicted binding sites in the promoter region of CCR6. Knocking down ARNTL using siRNA in CD4+ CCR6+ cells from adult blood or using Arntl knockout mice have demonstrated a role for this factor in regulating CCR6 as well as other Th-17 cell associated genes. Studying ARNTL and other clock proteins in Th17 cells opens a new line of investigation into relationships between the molecular control of circadian rhythms and the regulation of adaptive immunity, which may have implications for immune homeostasis and Th17-cell associated disease. Supported by Intramural Research Program, NIAID, NIH.