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The microbiota maintain homeostasis of liver-resident ??T-17 cells in a lipid antigen/CD1d-dependent manner.

ABSTRACT: The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing ?? T (??T-17) cells in various tissues. However, little is known regarding hepatic ??T cells that are constantly stimulated by gut commensal microbes. Here we show hepatic ??T cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic ??T-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver-resident ??T-17 cells; indeed, E. coli alone can generate ??T-17 cells in a dose-dependent manner. Liver-resident ??T-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic ??T-17 cell number. Moreover, the microbiota accelerate nonalcoholic fatty liver disease through hepatic ??T-17 cells. Thus, our work describes a unique liver-resident ??T-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens.

SUBMITTER: Li F

PROVIDER: S-EPMC5227332 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner.

Li Fenglei F Hao Xiaolei X Chen Yongyan Y Bai Li L Gao Xiang X Lian Zhexiong Z Wei Haiming H Sun Rui R Tian Zhigang Z

Nature communications 20170109

The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing γδ T (γδT-17) cells in various tissues. However, little is known regarding hepatic γδT cells that are constantly stimulated by gut commensal microbes. Here we show hepatic γδT cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic γδT-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver- ...[more]

PMID: 28067223

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Project description:Ildr2, a modifier of diabetes susceptibility in obese mice, is expressed in most organs, including islets and hypothalamus, with reduced levels in livers of diabetes-susceptible B6.DBA mice congenic for a 1.8 Mb interval of Chromosome 1. In hepatoma and neuronal cells, ILDR2 is primarily located in the endoplasmic reticulum membrane. We used adenovirus vectors that express shRNA or are driven by the CMV promoter, respectively, to knockdown or overexpress Ildr2 in livers of wild type and ob/ob mice. Livers in knockdown mice were steatotic, with increased hepatic and circulating triglycerides and total cholesterol. Increased circulating VLDL, without reduction in triglyceride clearance suggests an effect of reduced hepatic ILDR2 on hepatic cholesterol clearance. In animals that overexpress Ildr2, hepatic triglyceride and total cholesterol levels were reduced, and strikingly so in ob/ob mice. There were no significant changes in body weight, energy expenditure or glucose/insulin homeostasis in knockdown or overexpressing mice. Knockdown mice showed reduced expression of genes mediating synthesis and oxidation of hepatic lipids, suggesting secondary suppression in response to increased hepatic lipid content. In Ildr2-overexpressing ob/ob mice, in association with reduced liver fat content, levels of transcripts related to neutral lipid synthesis and cholesterol were increased, suggesting "relief" of the secondary suppression imposed by lipid accumulation. Considering the fixed location of ILDR2 in the endoplasmic reticulum, we investigated the possible participation of ILDR2 in ER stress responses. In general, Ildr2 overexpression was associated with increases, and knockdown with decreases in levels of expression of molecular components of canonical ER stress pathways. We conclude that manipulation of Ildr2 expression in liver affects both lipid homeostasis and ER stress pathways. Given these reciprocal interactions, and the relatively extended time-course over which these studies were conducted, we cannot assign causal primacy to either the effects on hepatic lipid homeostasis or ER stress responses.

Dataset Information

The microbiota maintain homeostasis of liver-resident ??T-17 cells in a lipid antigen/CD1d-dependent manner.

Publications

The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner.

Similar Datasets

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