Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis
Aaron Douglas, Brenneth Stevens, Miguel Rendas, Harry Kane, Evan B. Lynch, Britta Kunkemoeller, Karl A. Wessendorf-Rodriguez, Emily A. Day, Caroline E. Sutton, Martin Brennan, Katie O’Brien, Ayano C. Kohlgruber, Hannah Prendeville, Amanda Garza, Luke O'neill, Kingston H. G. Mills, Christian M. Metallo, Henrique Veiga‐Fernandes, Lydia Lynch
Abstract
The circadian rhythm of the immune system helps to protect against pathogens1–3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4–7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells—including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells—are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αβ or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a−/−Il17f−/− mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17. Innate IL-17-producing T cells—in particular, adipose γδ17 T cells—are enriched in molecular-clock genes, and the circadian expression of IL-17A and RORγt by these cells has a role in maintaining local homeostasis and regulating lipogenesis.