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

Magar Ghazarian, Xavier S. Revelo, Mark K. Nøhr, Helen Luck, Kejing Zeng, Helena Lei, Sue Tsai, Stephanie A. Schroer, Yoo Jin Park, Melissa Hui Yen Chng, Lei Shen, June Ann D’Angelo, Peter Horton, William C. Chapman, Diane Brockmeier, Minna Woo, Edgar G. Engleman, Oyedele Adeyi, Naoto Hirano, Tianru JinAdam J. Gehring, Shawn Winer, Daniel A. Winer

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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 IFN protein, whereas IFNR1−/− mice or CD8-specific IFNR1−/− chimeric mice are protected from disease. IFNR1 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.

Original languageEnglish
Article numbereaai7616
JournalScience immunology
Volume2
Issue number10
DOIs
StatePublished - 2017

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