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

Abstract

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 humanspecific 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.

A single-cell transcriptomic atlas characterizes liver non-parenchymal cells in healthy and diseased mice

“…Similarly, 30,120 T cells were divided into seven subtypes, including natural killer T (NKT) cells (T1), CD4 + T cells (T2, T3, and T4), CD8 + T cells (T5 and T6), and specific Ramp1 + T cells (T7), with distinct transcriptomic signatures (Figure 4A-C). In particular, the number of subtypes T3 (CD4 + Foxp3 + regulatory T cells) and T6 (effector memory CD8 + T cells) was notably elevated in the HF-MCD group, which consistent with previous studies that activated CD4 + and CD8 + T cells is essential for the progression of NASH and liver fibrosis (Figure 4C) (14,36). T4 and T5 are naive CD4 + and CD8 + T cells with high expression of Ccr7 and Sell (10).…”

The Role of the Gut-Liver Axis in Metabolic Dysfunction-Associated Fatty Liver Disease

“…Humanized mouse models of dietinduced MAFLD showed a remarkable liver infiltration of CD4+, CD8+T cells and macrophages (CD68+), which were largely confined to fibrotic regions. Conversely, depletion of CD4+T cells abrogated diet-induced inflammatory response and liver fibrosis development (77). Further studies have shown that blocking integrin receptor a4b7-mediated recruitment of CD4+ T cells to the intestine and liver, not only attenuates hepatic inflammation and fibrosis, but also improves metabolic alterations associated with MAFLD (78).…”

Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis

“…The use of IL-17A–deficient mice models has been shown to improve/resist to the development of steatohepatitis, a major risk factor of fibrosis ( 101 , 102 ). Humanized mice on high fat diet with induced NAFLD develop liver fibrosis that is mediated by CD4 + IL17A + cells ( 103 ). The depletion of CD4 + cells in these mice reduced fibrosis and inflammation but not steatosis.…”