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Sci Immunol. 2017 Apr 21;2(10). pii: eaai7616. doi: 10.1126/sciimmunol.aai7616.

Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome.

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Division of Cellular and Molecular Biology, Diabetes Research Group, Toronto General Research Institute, University Health Network, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 3B3, Canada.
Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94205, USA.
Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Methodist University Hospital Transplant Institute, Memphis, TN 38104, USA.
Division of Abdominal Transplant, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Division of Abdominal Transplant, Washington University School of Medicine, St. Louis, MO 63110, USA.
Mid-America Transplant Services, St. Louis, MO 63110, USA.
Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada.
Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario M5G 2C4, Canada.
Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada.


Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, non-alcoholic 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 which links to glucose dysregulation. Accumulation and activation of these cells are largely supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice upregulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, while IFNαR1-/- mice, or CD8-specific IFNαR1-/- chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, while CD8+ T cells and IFN-I responses correlate with NAFLD activity 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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