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CD4 + T Cells Mediate the Development of Liver Fibrosis in High Fat Diet-Induced NAFLD in Humanized Mice

  • Her, Zhisheng1
  • Tan, Joel Heng Loong1
  • Lim, Yee-Siang2
  • Tan, Sue Yee1
  • Chan, Xue Ying1
  • Tan, Wilson Wei Sheng1
  • Liu, Min1
  • Yong, Kylie Su Mei1
  • Lai, Fritz1
  • Ceccarello, Erica1, 3
  • Zheng, Zhiqiang1
  • Fan, Yong4
  • Chang, Kenneth Tou En5
  • Sun, Lei6
  • Chang, Shih Chieh7
  • Chin, Chih-Liang8
  • Lee, Guan Huei9
  • Dan, Yock Young9
  • Chan, Yun-Shen2
  • Lim, Seng Gee9
  • And 3 more
  • 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A ∗STAR), Singapore , (Singapore)
  • 2 Genome Institute of Singapore, Agency for Science, Technology and Research (A ∗STAR), Singapore , (Singapore)
  • 3 Programme in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore , (Singapore)
  • 4 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou , (China)
  • 5 Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore , (Singapore)
  • 6 Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore , (Singapore)
  • 7 Laboratory of Molecular Physiology, Infection and Immunity Theme, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore , (Singapore)
  • 8 Translational Biomarkers, Merck Research Laboratories, MSD, Singapore , (Singapore)
  • 9 Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, Singapore , (Singapore)
  • 10 Department of Reproductive Medicine, KK Women’s and Children’s Hospital, Singapore , (Singapore)
  • 11 Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore , (Singapore)
  • 12 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore , (Singapore)
Published Article
Frontiers in Immunology
Frontiers Media SA
Publication Date
Sep 11, 2020
DOI: 10.3389/fimmu.2020.580968
PMID: 33013934
PMCID: PMC7516019
PubMed Central


Non-alcoholic fatty liver disease (NAFLD) has been on a global rise. While animal models have rendered valuable insights to the pathogenesis of NAFLD, discrepancy with patient data still exists. Since non-alcoholic steatohepatitis (NASH) involves chronic inflammation, and CD4+ T cell infiltration of the liver is characteristic of NASH patients, we established and characterized a humanized mouse model to identify human-specific immune response(s) associated with NAFLD progression. Immunodeficient mice engrafted with human immune cells (HIL mice) were fed with high fat and high calorie (HFHC) or chow diet for 20 weeks. Liver histology and immune profile of HIL mice were analyzed and compared with patient data. HIL mice on HFHC diet developed steatosis, inflammation and fibrosis of the liver. Human CD4+ central and effector memory T cells increased within the liver and in the peripheral blood of our HIL mice, accompanied by marked up-regulation of pro-inflammatory cytokines (IL-17A and IFNγ). In vivo depletion of human CD4+ T cells in HIL mice reduced liver inflammation and fibrosis, but not steatosis. Our results highlight CD4+ memory T cell subsets as important drivers of NAFLD progression from steatosis to fibrosis and provides a humanized mouse model for pre-clinical evaluation of potential therapeutics.

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