Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis

• 成果类型: Article
• 署名作者: Douglas, Aaron; Stevens, Brenneth; Rendas, Miguel; Kane, Harry; Lynch, Evan; Kunkemoeller, Britta; Wessendorf-Rodriguez, Karl; Day, Emily A.; Sutton, Caroline; Brennan, Martin; O'Brien, Katie; Kohlgruber, Ayano C.; Prendeville, Hannah; Garza, Amanda E.; O'Neill, Luke A. J.; Mills, Kingston H. G.; Metallo, Christian M.; Veiga-Fernandes, Henrique; Lynch, Lydia
• 署名单位: Trinity College Dublin; Fundacao Champalimaud; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Salk Institute; Princeton University; Princeton University; Ludwig Institute for Cancer Research
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3776
• DOI: 10.1038/s41586-024-08131-3
• 发表日期: 2024-12-05
• 页码: 206-214
• 关键词: diet-induced obesity; circadian clock; shift work; mice; tissue; architecture; temperature; expression; regulators; HEALTH

摘要

The circadian rhythm of the immune system helps to protect against pathogens(1-3); 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 homeostasis(4-7). Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including gamma delta T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFN gamma-producing counterparts. We reveal that IL-17-producing.d (gamma delta 17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for ROR gamma t and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1(Delta Vav1)) affects the production of IL-17 by adipose gamma delta 17 T cells, but not cytokine production by alpha beta or IFN gamma-producing gamma delta (gamma delta(IFN gamma)) 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.