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 Jin; Adam J. Gehring; Shawn Winer; Daniel A. Winer

doi:10.1126/sciimmunol.aai7616

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

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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 language	English (US)
Article number	eaai7616
Journal	Science Immunology
Volume	2
Issue number	10
DOIs	https://doi.org/10.1126/sciimmunol.aai7616
State	Published - 2017
Externally published	Yes

Bibliographical note

Funding Information:
We thank P. Ohashi for discussing the results. All other authors discussed the results and/or reviewed the manuscript. This work was supported, in part, by the Canadian Institutes of Health Research (CIHR) grants 119414, 132562, 142708, and 148385 (to D.A.W.); Canadian Diabetes Association (CDA) grants OG-3-15-5014 and CS-5-12-3886 (to D.A.W.); and J.P. Bickell Foundation Grant (to D.A.W.). D.A.W. received a Canada Research Chair and the Ontario Ministry of Innovation Early Researcher Award. M.G. received a CIHR Canada Graduate Scholarship–Master’s Program award. M.K.N. is the recipient of an Alfred Benzon Foundation Postdoctoral Fellowship, and X.S.R. is the recipient of a CDA Postdoctoral Fellowship Award.

Publisher Copyright:
2017 © The Authors.

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Ghazarian, M., Revelo, X. S., Nøhr, M. K., Luck, H., Zeng, K., Lei, H., Tsai, S., Schroer, S. A., Park, Y. J., Chng, M. H. Y., Shen, L., D’Angelo, J. A., Horton, P., Chapman, W. C., Brockmeier, D., Woo, M., Engleman, E. G., Adeyi, O., Hirano, N., ... Winer, D. A. (2017). Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome. Science Immunology, 2(10), Article eaai7616. https://doi.org/10.1126/sciimmunol.aai7616

Ghazarian, M, Revelo, XS, Nøhr, MK, Luck, H, Zeng, K, Lei, H, Tsai, S, Schroer, SA, Park, YJ, Chng, MHY, Shen, L, D’Angelo, JA, Horton, P, Chapman, WC, Brockmeier, D, Woo, M, Engleman, EG, Adeyi, O, Hirano, N, Jin, T, Gehring, AJ, Winer, S & Winer, DA 2017, 'Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome', Science Immunology, vol. 2, no. 10, eaai7616. https://doi.org/10.1126/sciimmunol.aai7616

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title = "Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome",

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.",

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note = "Funding Information: We thank P. Ohashi for discussing the results. All other authors discussed the results and/or reviewed the manuscript. This work was supported, in part, by the Canadian Institutes of Health Research (CIHR) grants 119414, 132562, 142708, and 148385 (to D.A.W.); Canadian Diabetes Association (CDA) grants OG-3-15-5014 and CS-5-12-3886 (to D.A.W.); and J.P. Bickell Foundation Grant (to D.A.W.). D.A.W. received a Canada Research Chair and the Ontario Ministry of Innovation Early Researcher Award. M.G. received a CIHR Canada Graduate Scholarship–Master{\textquoteright}s Program award. M.K.N. is the recipient of an Alfred Benzon Foundation Postdoctoral Fellowship, and X.S.R. is the recipient of a CDA Postdoctoral Fellowship Award. Publisher Copyright: 2017 {\textcopyright} The Authors.",

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AU - Revelo, Xavier S.

AU - Nøhr, Mark K.

AU - Luck, Helen

AU - Zeng, Kejing

AU - Lei, Helena

AU - Tsai, Sue

AU - Schroer, Stephanie A.

AU - Park, Yoo Jin

AU - Chng, Melissa Hui Yen

AU - Shen, Lei

AU - D’Angelo, June Ann

AU - Horton, Peter

AU - Chapman, William C.

AU - Brockmeier, Diane

AU - Woo, Minna

AU - Engleman, Edgar G.

AU - Adeyi, Oyedele

AU - Hirano, Naoto

AU - Jin, Tianru

AU - Gehring, Adam J.

AU - Winer, Shawn

AU - Winer, Daniel A.

N1 - Funding Information: We thank P. Ohashi for discussing the results. All other authors discussed the results and/or reviewed the manuscript. This work was supported, in part, by the Canadian Institutes of Health Research (CIHR) grants 119414, 132562, 142708, and 148385 (to D.A.W.); Canadian Diabetes Association (CDA) grants OG-3-15-5014 and CS-5-12-3886 (to D.A.W.); and J.P. Bickell Foundation Grant (to D.A.W.). D.A.W. received a Canada Research Chair and the Ontario Ministry of Innovation Early Researcher Award. M.G. received a CIHR Canada Graduate Scholarship–Master’s Program award. M.K.N. is the recipient of an Alfred Benzon Foundation Postdoctoral Fellowship, and X.S.R. is the recipient of a CDA Postdoctoral Fellowship Award. Publisher Copyright: 2017 © The Authors.

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N2 - 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.

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

Abstract

Bibliographical note

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