近日，爱尔兰都柏林圣三一学院 Lydia Lynch及其研究小组，揭示了γδ T细胞节律性产生IL-17维持脂肪从头生成。2024年10月30日出版的《自然》发表了这项成果。

据了解，免疫系统的昼夜节律有助于抵御病原体。然而，昼夜节律在免疫稳态中的作用尚不清楚。先天T细胞是组织驻留淋巴细胞，在组织稳态中起关键作用。

研究人员通过单细胞RNA测序、分子钟报告和遗传操作来证明，先天产生IL-17的T细胞——包括γδ T细胞、不变自然杀伤T细胞和粘膜相关不变T细胞——与产生IFNγ的T细胞相比，分子钟基因富集。研究组发现，特别是产生IL-17的γδ (γδ 17) T细胞，依赖于分子钟来维持脂肪组织的稳态，并且在脂肪库中表现出RORγt和IL-17A的昼夜节律，其在夜间达到峰值。

在小鼠中，CD45区（Bmal1^?Vav1）分子钟的缺失会影响脂肪γδ17 T细胞产生IL-17，但不会影响αβ或产生IFNγ的γδ (γδ ^IFNγ) T细胞产生细胞因子。昼夜节律的IL-17对脂肪组织的新生脂肪形成至关重要，脂肪细胞特异性缺乏IL-17受体C （IL-17RC）的小鼠在新生脂肪形成方面存在缺陷。

体内的全身代谢分析表明，Il17a^-/-Il17f^-/-小鼠（缺乏IL-17A和IL-17F的表达）在其新生脂肪生成的昼夜节律中存在缺陷，这导致其全身代谢节律和核心体温节律受到破坏。本研究确定了IL-17在全身代谢稳态中的关键作用，并表明从头脂肪生成是IL-17的主要靶点。

附：英文英文

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

Author: Douglas, Aaron, Stevens, Brenneth, Rendas, Miguel, Kane, Harry, Lynch, Evan, Kunkemoeller, Britta, Wessendorf-Rodriguez, Karl, Day, Emily A., Sutton, Caroline, Brennan, Martin, OBrien, Katie, Kohlgruber, Ayano C., Prendeville, Hannah, Garza, Amanda E., ONeill, Luke A. J., Mills, Kingston H. G., Metallo, Christian M., Veiga-Fernandes, Henrique, Lynch, Lydia

Issue&Volume: 2024-10-30

Abstract: The circadian rhythm of the immune system helps to protect against pathogens1,2,3; 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 homeostasis4,5,6,7. 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 (Bmal1Vav1) 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.

DOI: 10.1038/s41586-024-08131-3

Source: https://www.nature.com/articles/s41586-024-08131-3