Decoding the role of immune T cells: A new territory for improvement of metabolic-associated fatty liver disease

Abstract

Metabolic-associated fatty liver disease (MAFLD) is a new emerging concept and is associated with metabolic dysfunction, generally replacing the name of nonalcoholic fatty liver disease (NAFLD) due to heterogeneous liver condition and inaccuracies in definition. The prevalence of MAFLD is rising by year due to dietary changes, metabolic disorders, and no approved therapy, affecting a quarter of the global population and representing a major economic problem that burdens healthcare systems. Currently, in addition to the common causative factors like insulin resistance, oxidative stress, and lipotoxicity, the role of immune cells, especially T cells, played in MAFLD is increasingly being emphasized by global scholars. Based on the diverse classification and pathophysiological effects of immune T cells, we comprehensively analyzed their bidirectional regulatory effects on the hepatic inflammatory microenvironment and MAFLD progression. This interaction between MAFLD and T cells was also associated with hepatic-intestinal immune crosstalk and gut microbiota homeostasis. Moreover, we pointed out several T-cell-based therapeutic approaches including but not limited to adoptive transfer of T cells, fecal microbiota transplantation, and drug therapy, especially for natural products and Chinese herbal prescriptions. Overall, this study contributes to a better understanding of the important role of T cells played in MAFLD progression and corresponding therapeutic options and provides a potential reference for further drug development.

Keywords: T cells; drug therapy; immunoregulation; intestinal flora; metabolic‐associated fatty liver disease.

Figure 1

The general background summary of MAFLD and immunocytes. (A) The liver of MAFLD. (B) The proportion of prevalence of common liver diseases. (C) Timeline of T cell development. MAFLD, metabolic‐associated fatty liver disease.

Figure 2

The homeostasis of Th1‐Th2 cells plays a decisive role in the progression of MAFLD. (A) Imbalance of Th1 and Th2 cells is accompanied by multicellular crosstalk. (B) Hepatocytes are impacted by disordering the proportion of Th1 and Th2 cells and their crucial inflammatory factors in MAFLD. Th1 cells upregulated the level of inflammatory cytokines and receptors, exacerbated hepatitis and lipid deposition, and even participated in the process of HCC. In addition, Th2 cells antagonized Th1 cells response and inhibited inflammation through anti‐inflammatory cytokines.

Figure 3

Changing the balance of Th22‐Th17‐Treg cells is one of the crucial approaches to deteriorate and improve MAFLD. The imbalance of Th22‐Th17‐Treg cells homeostasis exacerbated inflammation and fibrosis, or even gut dysbacteriosis by proinflammatory related factors, but was reversed through the treatment of drugs and microRNA, especially traditional Chinese medicine, probiotics, gene editor, or adoptive cell transfer (ACT)

Figure 4

CD8⁺ T cells play different regulatory roles and influence metabolic dysregulation. CD8⁺ T cells migrated to the liver and promoted diet‐induced MAFLD through binding to the Pro‐inflammatory chemokine receptor axis or affecting other immune cells (macrophages, neutrophils) response, but inflammatory damage was ameliorated by treatment with several anti‐inflammatory drugs. However, in special cases, CD8 + T cells inhibited fibrosis and even improved MAFLD either by restoring the balance of gut microbiota or combination therapy with drugs

Figure 5

NKT cells exert both positive and negative effects on MAFLD. NKT cells have more complex immune properties and are a double‐edged sword for MAFLD. Even in the same gene knockout animal model of MAFLD, NKT cells also show contrasting experimental results that are the promotion of lipid accumulation and inflammatory infiltration by proinflammatory immune cells and factors, but on the other hand, the inhibition of MAFLD by anti‐inflammatory factors. Gene editing, drugs and probiotics are effective ways to improve metabolic damage via regulating NKT cells. Some materials of the illustrations are quoted from BioRender.