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Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05 Page 7 of 15

immunoregulatory cytokines, such as IFN-γ and TNF-α, to activate T cells [97,98] . Recent studies demonstrate
that liver-resident CD56 (bright) NK cells, which show increased expression of NKG2D and TRAIL and
low production of IFN-γ, represent a cell population adapted for tolerogenic liver microenvironment and
inducible anti-viral immunity [99,100] . Accumulating evidence illustrates that function of NK cells is impaired in
CHB and HBV progressed diseases. NK cells in blood from CHB patients express higher level of suppressive
cell surface molecules and cytokines, such as Tim-3, PD-1 and IL-10, which is induced by HBsAg-mediated
increase of monocytes [101,102] . Besides, HBV nucleic acids-contained exosomes entering into NK cells inhibit
expression of pattern-recognition receptors and thus NF-κB and p38 MAPK pathways, which results in
dysfunction of NK cells [103] . Furthermore, intrahepatic NK cells-mediated apoptosis of hepatic stellate
cells (HSCs) is reversed via blockade of TGF-β in HBV-infected liver cirrhosis patients, which leads to
impairment of anti-fibrosis capacity in NK cells [104] . In HBV-associated HCC, LINC01149 variant upregulates
MICA expression through serving as miR-128-3p sponge to recruit NK cells to lyse infected cells, which
process releases highly soluble MICA and thus induces exhaustion of NK cells [105] .

IL-15 is crucial for homeostasis of NK cells. Deficiency of IL-15 or IL-15Rα inhibits high fat diet-induced
accumulation of lipids and inflammation in liver [106] , which probably suggests dysregulation of NK cells
involving in NAFLD progression. Although NK cells is a cell population with cytotoxicity in infected
tissues, these cells convert to less cytotoxic ILC1-like phenotype in NAFLD, which probably protect obese
liver from severe NAFLD but dampened capability to kill cancer cells [107] . In advanced stages of fibrosis in
NAFLD accompanied by insulin resistance, the ability of NK cells to restrain HSCs is impaired, mediated by
low expression of insulin receptors, which leads to deterioration of the liver and fibrosis [108] . Furthermore,
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NKp46 NK cells, as immunoregulatory cells, induce polarization of hepatic macrophages towards M1-like
phenotype via IFN-γ, which prevents NASH progression to fibrosis [109] .

T cells
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T cells represent the major adaptive lymphocytes in transformation from inflammation to cancer. CD8
T cells frequently show restricted proliferation and exhausted function with high expression of inhibitory
checkpoint molecules such as CTLA-4, PD-1 and TIM-3 in CHB and HBV-HCC. High expression of PD-1
on HBV-specific T cells or B cells induces exhaustion of T cells or reduced antibodies production, which is
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partially reversed by PD-1 blockade [110-112] . In HCC tissue, there exist CD8 T cells expressing different levels
of PD-1. The population with high-level PD-1 expresses TIM-3 and/or LAG-3 and produce limited IFNγ and
[113]
TNFα when exposed to anti-CD3 . Beyond, thymocyte selection associated high mobility group box (TOX)
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in CD8 T cells promotes PD-1 translocation to cell surface by regulating endocytic recycling of PD-1 [114] .
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Abundant exhausted CD8 T cells and Tregs exist and potentially clonally expand in cancerous tissues
from HCC patients [115] , contributing to evasion of tumor cells from immune surveillance. However, several
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studies illustrate that CD8 T cells potentiate to promote persistent hepatic inflammation susceptible to HCC
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development when HBV-specific CD8 T cells stay in activation but lack of capability to constrain virus
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replication [116] . Consistently, CD8 T cells possess dual functions in progression of NAFLD-related HCC.
In diet-induced obese mice, CD8 T cells are recruited to liver to promote insulin resistance and glucose
+
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metabolism, leading to steatohepatitis [117] . Meanwhile, another study demonstrates that activation of CD8 T
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cells is suppressed by liver-resident immunoglobulin-A-producing (IgA ) cells, which express high levels of
PD-L1 and IL-10 [118] .
+
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Compared to CD8 T cells, HBV-specific CD4 cytotoxic cells in PBMCs from HBV-associated HCC present
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at the similar level, but display weaker cytolysis capability and suppress cytotoxicity of CD8 T cells in the
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absence of Tregs [119] . The antigen-experienced T cells, CD4 follicular helper T (Tfh) cells diminish HBV via
response to HBsAg, which is impaired by CTLA-4-mediated Treg suppression [120] . Contrary with CTLA-4,
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increased expression of co-stimulatory molecule OX40 on peripheral CD4 T cells is associated with HBV