Table 1.
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] |