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

Condition
Cell type	Healthy Liver	References	Fibrosis and chronic inflammation	References	Hepatocellular carcinoma	References
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, 124–126]
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	[96–98, 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, 34–37, 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]