Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma - PubMed (original) (raw)

Review

Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Petra Hirsova et al. Front Endocrinol (Lausanne). 2021.

Abstract

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

Keywords: CD4/CD8 lymphocytes; HCC; Inflammation; NASH; T cells.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1

Nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of hepatic manifestations such as nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) that develop on the background of genetic and environmental factors including excess calories and sedentary lifestyle. NASH is a progressive condition that can advance to cirrhosis and hepatocellular carcinoma. (Created with

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Figure 2

Role of T cells in the pathogenesis of NASH and NASH-related HCC. Current evidence suggests that CD8 T cells, CD4 T helper cells, and γδ T cells contribute to NASH pathogenesis. The role of NKT cells, MAIT cells, and Tregs in NASH is incompletely understood. In NASH-related HCC, a subset of activated and exhausted CD8 T cells promote tumorigenesis while the role of CD4 T cells in this process warrants further investigation. (Created with

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Figure 3

Main T cell subsets and their functions. Conventional T cells are broadly grouped into CD8 and CD4 T cell subsets with diverse functions during an immune response. In general, CD8 cytotoxic T cells directly kill cancerous or infected cells, while CD4 T cells regulate the immune response to a particular antigen. CD4 T cells can be classified as T helper (Th) cells or regulatory T cells (Tregs). Differentiated CD4 T cell subsets are marked by the expression of the lineage-specific transcription factors T-bet (Th1), GATA3 (Th2), RORγt (Th17), and FOXP3 (Tregs), which are critical for their differentiation and function. Innate-like T cells are a highly diverse group of cells including natural killer T (NKT) cells, gamma delta (γδ) T cells, or mucosal-associated invariant T (MAIT) cells. (Created with

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Figure 4

Mechanisms by which T cells can promote NASH and HCC pathogenesis. Hepatic CD8 T cells in NASH secrete cytokines that promote hepatic stellate cell (HSC) activation and tissue inflammation. NASH-associated CD8 T cells can also cause non-specific (antigen-independent) cell death of hepatocytes. T helper cells, Th17 and Th1, and γδ T cells secrete effector cytokines during NASH, contributing to inflammatory tissue milieu. Loss of T cell protein tyrosine phosphatase (TCPTP) in hepatocytes leads to STAT-3-dependent secretion of CXCL9 and liver tumorigenesis. Programmed cell death protein 1 (PD-1)+ CD8 T cells, Tregs, and cytokine IL-17 promote HCC development, while CD4 T cells overall may decrease tumor burden and control tumor size. (Created with

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Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma - PubMed (original) (raw)