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

Aaron Douglas, Brenneth Stevens, Miguel Rendas, Harry Kane, Evan Lynch, Britta Kunkemoeller, Karl Wessendorf-Rodriguez, Emily A. Day, Caroline Sutton, Martin Brennan, Katie O’Brien, Ayano C. Kohlgruber, Hannah Prendeville, Amanda E. Garza, Luke A. J. O’Neill, Kingston H. G. Mills, Christian M. Metallo, Henrique Veiga-Fernandes and Lydia Lynch ()
Additional contact information
Aaron Douglas: Trinity College Dublin
Brenneth Stevens: Trinity College Dublin
Miguel Rendas: Champalimaud Centre for the Unknown
Harry Kane: Trinity College Dublin
Evan Lynch: Trinity College Dublin
Britta Kunkemoeller: Harvard Medical School
Karl Wessendorf-Rodriguez: Salk Institute for Biological Studies
Emily A. Day: Trinity College Dublin
Caroline Sutton: Trinity College Dublin
Martin Brennan: Trinity College Dublin
Katie O’Brien: Trinity College Dublin
Ayano C. Kohlgruber: Harvard Medical School
Hannah Prendeville: Trinity College Dublin
Amanda E. Garza: Harvard Medical School
Luke A. J. O’Neill: Trinity College Dublin
Kingston H. G. Mills: Trinity College Dublin
Christian M. Metallo: Salk Institute for Biological Studies
Henrique Veiga-Fernandes: Champalimaud Centre for the Unknown
Lydia Lynch: Trinity College Dublin

Nature, 2024, vol. 636, issue 8041, 206-214

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08131-3

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