Research ArticleMETABOLIC DISEASE

Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome

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Science Immunology  21 Apr 2017:
Vol. 2, Issue 10, eaai7616
DOI: 10.1126/sciimmunol.aai7616

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Liver T cells—The missing link in obesity-associated diabetes

Obesity is associated with increased risk of developing a range of disorders including cardiovascular diseases and type 2 diabetes. In obese individuals, accumulation of fat in the liver, termed nonalcoholic fatty liver disease (NAFLD), has been linked to the development of insulin resistance. Ghazarian et al. report that type I interferon–driven activation of CD8+ T cells in the liver correlates with insulin resistance in patients with NAFLD and in mouse models of obesity. Furthermore, the authors found that gut microbiome plays an important role in driving inflammation in the livers of obese mice. Their studies add to the growing recognition of the immune axis in metabolic disorders associated with obesity.

Abstract

Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, whereas IFNαR1−/− mice or CD8-specific IFNαR1−/− chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, whereas CD8+ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

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