Crucial role of T cells in NAFLD-related disease: A review and prospect

Abstract

Nonalcoholic fatty liver disease (NAFLD) includes a series of hepatic manifestations, starting with liver steatosis and potentially evolving towards nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis or even hepatocellular carcinoma (HCC). Its incidence is increasing worldwide. Several factors including metabolic dysfunction, oxidative stress, lipotoxicity contribute to the liver inflammation. Several immune cell-mediated inflammatory processes are involved in NAFLD in which T cells play a crucial part in the progression of the disease. In this review, we focus on the role of different subsets of both conventional and unconventional T cells in pathogenesis of NAFLD. Factors regarding inflammation and potential therapeutic approaches targeting immune cells in NASH are also discussed.

Keywords: CD4+ T cells; CD8+ T cells; hepatocellular carcinoma (HCC); nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH).

Figure 1

Role of CD4⁺ T cell. Different sets of CD4⁺ T cells including Th1, Th2, Th17, Th22, Treg cells involve in the regulation of NASH and NASH-induced HCC mainly through secretion of cytokines and interaction with other cells. Th1 cells are featured with secretion of IFN-γ, which can further induce apoptosis and cell cycle arrest of hepatocyte, activation of kupffer cells (KCs), production of CXCL20 and chemotaxis of CXCR3⁺ T cells in a CXCL10-dependent manner, thus accelerating the evolution of NASH. The exact role of Th2 cells releasing IL-4/13/15 in NASH remains controversial, on one hand, they play an anti-inflammatory part in NASH, on the other hand, they aggravate fibrosis in NASH. Moreover, there still have some debate over the effect of Th17 cells on NASH. Th17 cells can secret IL-17 which result in recruitment of macrophages via releasement of CXCL10, activation of HSC, upregulation of pro-fibrotic genes and lipotoxic effect of FFAs in a JNK-dependent way, thus facilitating the development of NASH. However, several researches have demonstrated that functional blockade of IL-17 enhances NAFLD. Th22 cells characterized by release of IL-22 have been verified as a protective factor of NASH. Th22 cells can suppress lipotoxicity and inflammation through PI3K/Akt and STAT3 pathway respectively. What’s more, MT, an anti-oxidant enzyme, can be upregulated by Th22 cells which further restrains hepatic oxidative stress and inflammatory function of hepatocyte-derived extra cellular vesicles. Meanwhile, Th22 cells involve in upregulation of anti-apoptosis genes and downregulation of genes associated with lipid biosynthesis. Treg cells play a complex role in NASH, they can not only promote fibrosis through release of TGF-β, but also inhibit fibrosis via secretion of IL-10. Treg cells lead to exacerbation of NASH-induced HCC through suppression of tumor-infiltrating CD8⁺ T cells and Th1 cells. Th1 cells have been identified as anti-tumor cells through release of IFN-γ, meanwhile Th17 cells have been recognized as pro-tumor cells in NASH-induced HCC. However, a recent study indicated that a predominant Th1 inflammatory pattern contributes to HCC while shifting to a Th17 inflammatory pattern inhibits tumor progression. The exact role of each subset of CD4⁺ T cells in NASH and NASH-induced HCC need further investigation.

Figure 2

Role of CD8⁺ T cell. CD8⁺ T cells expressing various receptors on the cell surface play a complex role in the evolvement of NASH and NASH-induced HCC. Breaking down of the balance between damage and repairment functions of CD8⁺ T cells may result in the exacerbation of diseases. CD8⁺ Trm cells induce the recruitment of HSC in a CCR5-dependent manner and further lead to apoptosis of HSC through FasL-Fas thus inhibiting fibrosis in NASH. CD8⁺ T cells play an anti-inflammatory part in NASH through secretion of perforin which can not only induce cytotoxic reaction in M1 monocytes and macrophages but also promote apoptosis of CD8⁺ T cells producing pro-inflammatory cytokines. Upregulation of PD1 on CD8⁺ T cells restricts proliferation and degranulation of CD8⁺ T cells, meanwhile, increased 2B4 on CD8⁺ T cells leads to reduced proliferation rate and decreased secretion of inflammatory cytokines, thus relieving liver damage. However, CD8⁺ T cells have been reported as a promoter of NASH. Mechanically, CD8⁺ T cells can induce pyroptotic-like cell death in macrophages and hepatocytes, result in impaired insulin signaling through release of IFN-γ/TNF-α, and lead to liver damage in a LTβR-independent manner. Moreover, CXCR6⁺CD8⁺ T cells accelerate apoptosis of hepatocytes dependent of FasL-Fas which facilitate NASH. CD8⁺ Tc cells, mainly effector cells of CD8⁺ T cells, can not only function as immune surveillance cells to suppress NASH-induce HCC but also act as pro-tumor cells through interacting with NKT cells to activate LTβR, NF-kB pathways and inducing exacerbation of tissue damage. CD8⁺ Trm cells, a kind of CD8⁺ memory cells, have been verified as pro-tumor cells in NASH-induced HCC. However, evidence has shown that CD8⁺ Trm cells can restrict the evolution of fibrosis in NASH which probably limits the transition of NASH into HCC.

Figure 3

Role of unconventional T cell. Unconventional T cells like NKT, MALT, γδT cells participate in the development of NAFLD. γδT cells have been proven to facilitate the development of NAFLD through secretion of IL-17 and IFN-γ which can lead to cytotoxic activity on target cells. What’s more, IL-17 released by γδT cells can induce activation of hepatic stellate cells (HSCs) and KCs thus promoting fibrosis in NASH. However, conflicting results regarding the role of NKT and MALT cells in NAFLD have been exhibit. NKT cells have been reported as protective factors of NASH, mechanically, they can not only restrain diet-induced obesity and metabolic dysfunction but also limit inflammation. However, NKT cells can induce pro-inflammatory environment and steatosis dependent of TRAIL and LIGHT respectively. Meanwhile, fibrosis is accelerated partly attributed to release of Hh ligands/OPN by NKT cells. On one hand, MALT cells induce the differentiation of monocytes and macrophages into anti-inflammatory phenotype thus inhibiting development of NASH. On the other hand, MALT cells can not only induce the accumulation of hepatic fibrogenic cells which further result in fibrosis, but also promote inflammation through differentiation of hepatic fibrogenic cells into pro-inflammatory phenotype dependent of TNF-γ and release of IL-17. Last but not the least, NKT cells functioning as immune surveillance cells are crucial in suppressing NASH-induced HCC.