Table 1 Immune cell functions and alterations across the spectrum of healthy liver, fibrosis, and hepatocellular carcinoma

CD8⁺ T cell

Provide protection against infection

[32]

Progressive dysfunction and exhaustion, PD-1 upregulation with chronic inflammation and viral infection

[90]

Anti-tumor antigen-specific responses detected; Progressive dysfunction and exclusion from tumors, upregulated exhaustion markers, low production of granzyme B and perforin, decreased proliferation

[96, 98, 116, 124,125,126]

CD4⁺ Treg

Antigen-specific tolerance; Readily expand following interaction with HSCs, Kupffer cells, and LSECs

[25, 26, 37]

Secrete IL-10 and TGFβ; Inhibit CD8⁺ T cell responses; Promote B cell activation and production of IgG through CD40-CD40L interaction

[84, 85]

Increased numbers of Tregs found within liver tumors; Suppress CD8⁺ T cell production of perforin and proliferation; Inhibit CD4⁺ effector T cell proliferation; Suppress NK function including cytotoxicity and IFNγ production

[96,97,98, 107]

CD4⁺ Th cell

Anti-microbial protective immunity; Regulators of pro- and anti-inflammatory signals

[32, 37]

Decreased numbers of naïve CD4⁺ T cells in circulation in cirrhotic patients; Increased numbers of Th17 cells, IL-17 can promote fibrosis via activation of stellate cells

[37, 83, 87, 88]

Elevated CD4/CD8 ratio predictive of recurrence free survival; Increased expression of PD-1 and CTLA-4, Decreased cytokine secretion in intra-tumoral CD4⁺ cells compared to peripheral blood CD4⁺ T cells

[96, 99]

B cell

Not well characterized, few B cells found in healthy liver

[32]

Role not as well-defined; found to be activated in chronic liver disease

[85]

Rarely found via IHC staining of liver tumors, IgA-producing cells suppress CD8⁺ T cells

[94, 113]

TCRγδ T cell

Recognition of peptide and non-peptide ligands; Innate-like and adaptive T cell protection from pathogens

[33]

Production of pro-inflammatory IL-17; Recruitment of CD8⁺ T cells and Th1 cells; Killing of HSCs; Promote monocyte differentiation into MDSCs

[37, 86]

Possible anti-tumor cytotoxicity

[118]

Kupffer cell

Induction of tolerance to commensal bacteria and food particles; Recruit Tregs; Recruitment and clearance of neutrophils; Stimulate T cell response to infection; Recruit and activate NK cells via IL-12 and cell:cell contact

[23, 28, 34,35,36,37, 39, 63]

Lose tolerogenic properties under inflammatory conditions; Secrete reactive oxygen species, TGFβ, PDGF, TNFα, and matrix metalloproteinases; Activate HSCs

[23, 33, 61, 65]

Protective against tumors via clearance of tumor cells; Suppression of T cell function via PD-L1 expression

[38, 111]

MAIT cell

Protection against bacteria; React to lipid antigens

[37, 43, 44]

Exhausted phenotype with upregulation of PD-1 and CTLA-4; Capable of activating HSCs

[92, 93]

Potential anti-tumor cytotoxicity; Excluded from tumors and found at higher frequencies in surrounding tissue

[44, 96]

NK cell

Anti-viral protection through cytokine production and cytotoxicity

[28]

Protect against fibrosis by killing of HSCs and production of IFNγ; Can induce liver injury by worsening inflammation

[27, 28, 33]

Cytotoxic to tumor cells; Impaired function (decreased granzyme and perforin, decreased cytotoxicity) and decreased in number in tumors and peripheral blood; Decreased expression of KIR2DL1 and KIR2DL3

[28, 94, 97, 100]

NK T cell

Th1-like phenotype in the presence of IL-12; Th2-like phenotype in the presence of IL-7. Type I NK T cells: Activate neutrophils and HSCs, cause hepatocyte death. Type II NK T cells: Suppress pro-inflammatory signaling pathways.

[28, 45, 46]

Type I NK T cells: Activation of HSCs and neutrophils, production of IFNγ and IL-4 can worsen inflammation

[45, 72]

Type I NK T cells associated with tumor control; Impaired cytotoxicity, decreased expression of KIR2DL1 and KIR2DL3

[71, 100]

Hepatic stellate cell

Express MHC I and II; Induce tolerance and anti-microbial immunity; PD-L1 expression leading to T cell apoptosis

[23, 39]

Differentiate to myofibroblasts; Secrete matrix metalloproteinases, extracellular matrix remodeling; Secrete IL-6, TNFα and TGFβ, Induce Th17 cells and Tregs

[39, 59, 61, 65, 88]

Induce MDSC and polarize monocytes to an immunosuppressive phenotype; Promote tumor growth

[42, 64]

Liver sinusoidal endothelial cell

Expression of MHC I and II; Activate CD4⁺ and CD8⁺ T cell responses; Induce tolerance via PD-L1 expression; Induction of Tregs

[35, 39, 40, 50]

Impaired antigen-processing and lower MHC II expression in the setting of fibrosis related to high levels of circulating endotoxin

[41]

Induce tolerance to tumor-derived antigens; decrease ability of dendritic cells to stimulate T cell responses

[42, 47]

Bone marrow-derived monocyte, macrophage, and dendritic cell

Promote tolerance to commensals and food particles; Stimulate T cell response to infection; More tolerogenic than activating in healthy liver

[39, 47]

Dysfunctional antigen presentation; Increased non-classical monocytes; Production of pro-inflammatory cytokines (TNFα, IL-6, IL-1)

[41, 77, 78, 82, 83]

Conversion to MDSC capable of suppressing effector T cells, inducing Tregs, and promoting tumor growth through pro-angiogenic cytokine production; Conversely, can control tumors via induction of antigen-specific T cell responses; Impaired ability to penetrate tumor tissue

[23, 42, 47, 64, 104]