Circadian Regulation of Regulatory T Cells in Visceral Adipose Tissue

Abstract

Regulatory T cells (Tregs) in non-lymphoid tissues provide critical brakes on inflammation and control tissue homeostasis. While tissue Tregs are phenotypically diverse, they may adopt common mechanisms to optimize their performance and survival. Upregulation of pathways related to circadian rhythms are a shared feature of tissue Tregs vis-à-vis their lymphoid-organ counterparts, although the diurnal regulation of Tregs and its consequences are controversial and poorly understood. Focusing on visceral adipose tissue (VAT) Tregs as a paradigmatic tissue-Treg population, we profiled diurnal variations in VAT and splenic Tregs in the presence and absence of core clock genes. VAT Tregs upregulated the expression of their core clock genes and amplified the rhythmicity of their expression profiles. VAT, but not splenic, Tregs exhibited diurnal variations in their activation state and mitochondrial oxidative metabolism. Bmal1 deficiency specifically in Tregs led to constitutive activation and poor oxidative metabolism in VAT, but not splenic, Treg populations. Disruption of cell-intrinsic core clock components resulted in a loss of fitness during competitive transfer and in response to high-fat-diet challenge. These results re-emphasize the striking divergence between tissue and lymphoid-organ Tregs, and argue for the importance of controlling circadian rhythms in experimental and therapeutic manipulations of Tregs.