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Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

ABSTRACT: Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although TSLP does not affect thymic Treg differentiation, TSLP receptor-deficient induced Treg cells derived from naïve CD4+ T cells are less activated in an adoptive transfer model of colitis. Mechanistically, TSLP activates induced Treg cells partially through mTORC1 activation and fatty acid uptake. Thus, TSLP modulates the activation status of induced Treg through the enhanced uptake of fatty acids to maintain homeostasis in the large intestine.

SUBMITTER: Kasuya T

PROVIDER: S-EPMC9887060 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

Kasuya Tadamichi T Tanaka Shigeru S Tamura Jun J Etori Keishi K Shoda Jumpei J Hattori Koto K Endo Yusuke Y Kitajima Masayuki M Kageyama Takahiro T Iwamoto Taro T Yokota Masaya M Iwata Arifumi A Suto Akira A Suzuki Kotaro K Suzuki Harumi H Ziegler Steven F SF Nakajima Hiroshi H

Scientific reports 20230130 1

Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although ...[more]

PMID: 36717741

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Project description:Background Endothelial cell injury, induced by dyslipidemia, is the initiation of atherosclerosis, resulting in an imbalance in endothelial fatty acid (FA) transport. Pigment epithelial-derived factor (PEDF) is an important regulator in lipid metabolism. We hypothesized that PEDF is involved in endothelium-mediated FA uptake under hyperlipidemic conditions. Methods and Results Circulating PEDF levels were higher in patients with atherosclerotic cardiovascular disease than in normal individuals. However, decreasing trends of serum PEDF levels were confirmed in both wild-type and apolipoprotein E-deficient mice fed a long-term high-fat diet. Apolipoprotein E-deficient/PEDF-deficient mice were generated by crossing PEDF-deficient mice with apolipoprotein E-deficient mice, and then mice were fed with 24, 36, or 48 weeks of high-fat diet. Greater increases in body fat and plasma lipids were displayed in PEDF-deficient mice. In addition, PEDF deficiency in mice accelerated atherosclerosis, as evidenced by increased atherosclerotic plaques, pronounced vascular dysfunction, and increased lipid accumulation in peripheral tissues, whereas injection of adeno-associated virus encoding PEDF exerted opposite effects. Mechanistically, PEDF inhibited the vascular endothelial growth factor B paracrine signaling by reducing secretion of protein vascular endothelial growth factor B in peripheral tissue cells and decreasing expression of its downstream targets in endothelial cells, including its receptors (namely, vascular endothelial growth factor receptor-1 and neuropilin-1), and FA transport proteins 3 and 4, to suppress endothelial FA uptake, whereas PEDF deletion in mice activated the vascular endothelial growth factor B signaling pathway, thus causing markedly increased lipid accumulation. Conclusions Decreasing expression of PEDF aggravates atherosclerosis by significantly impaired vascular function and enhanced endothelial FA uptake, thus exacerbating ectopic lipid deposition in peripheral tissues.

Dataset Information

Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

Publications

Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

Similar Datasets

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