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Regulatory T cells protect the neonatal liver and secure the hepatic circadian rhythm

Hofer, Ann-Cathrin

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Abstract

Regulatory T cells (Treg cells) play a crucial role in the immune system by controlling the establishment and maintenance of immune tolerance and homeostasis. Treg cells have been described to perform additional non-immunological functions beyond their classical functions in peripheral tissues. In this context, best examples are the specialized Treg cell population in visceral adipose tissue (VAT). The VAT-resident Treg cells gain the ability to control metabolic parameters. To further extent the concept of tissue-resident Treg cells, we aimed to analyze the phenotype and function of Treg cells in the liver tissue. We observed a significant accumulation of hepatic Treg cells in neonatal mice at around day 10 after birth. With progressive maturation of the mice the Treg frequency normalized. The neonatal hepatic Treg cells were highly proliferative as demonstrated by cell cycle measurements. Furthermore, the cells showed the characteristic Treg cell methylation pattern of the Foxp3 locus. The Treg cell accumulation in the neonatal liver occurred in an immature liver with strongly proliferating hepatocytes, a low-grad inflammatory signature and changes in key gene expression. Depletion of Treg cells with the associated loss of Treg-mediated immune control induced major changes in the liver, including increased expression of immune-related genes and genes regulating the circadian clock such as Rev-Erb-a or Per1. The circadian expression of approximately 400 genes in the liver was affected by the ablation of Treg cells. Our results indicate that Treg cells are important to secure the circadian rhythm of genes regulating the hepatic clock as well as clock-controlled genes. Furthermore, the presence of Treg cells is required for a normal expression of genes involved in liver metabolism, especially in the neonatal phase of the mice. Therefore, we propose that Treg cells do not only control the inflammatory state of the liver, but are also critical for the establishment and maintenance of liver homeostasis.

Item Type: Dissertation
Supervisor: Feuerer, Dr. Markus
Date of thesis defense: 12 September 2016
Date Deposited: 25 Oct 2016 08:02
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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