Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease

Table 1 Mucosal-associated invariant T cell characteristics and clinical implications

Feature	Characteristics	Clinical implications
Semi-invariant TCR	Semi-invariant α-chain in the TCR[3,7,72]; Canonical Vα7.2-Jα33 α-chain[3,7]; TRAV1-2/TRAJ33 encodes Vα7.2-Jα33[3]; Vβ6 and Vβ20 most common β-chains[61]; TRBV6, TRBV20-1 encode Vβ6, Vβ20[8,74]; Restricted length of CDRs[8,75]; CDR3β key to antigen recognition[10]	Limited number of antigens recognized[8,10]; Antigen diversity still possible[10]
MR1-restricted antigens	Class 1b antigen-presenting molecule[2,7]; Expressed on surface of APC[3]	MR1 limits antigens presented by APCs[10,114]
CD161	High surface expression[77-79]	Shared phenotypic marker with other T cells[78]
Cytokine receptors	IL-7, IL-12, IL-18, IL-23 receptors[80]	Multiple cytokines can activate MAIT cells[80,81]
Chemokine receptors	CCR5, CCR6, CCR9, CXCR6[59,62,77,82]	Chemokine-directed tissue migration[77]
Nuclear transcription factors	PLZF (also known as ZBTB16)[61,84,85]; RORγt[86]; T-bet[87,88,90,91]; ABCB1[11,62,83]	Control phenotype and functionality[84-88]; Direct development of memory phenotype[91]; Activate caspases and induce apoptosis[99]; Increase resistance to drugs, xenobiotics[11]
Cytokine production	IFN-γ, TNF-α, IL-17A, IL-22[11,17,81,102]; IL-13, IL-4, IL-5 (anti-inflammatory)[64,66]; IL-10 (mainly in adipose tissue)[106]	Pro-inflammatory and antiviral effects[17,81,102]; Anti-inflammatory effects[66,106]; Cross regulation of immune responses[64,65]
Effector phenotype	Granzyme B[4,107,108]; Perforin[4,74,108]	Antimicrobial and pro-apoptotic actions[4]; Eliminates infected or altered cells[4,107,108]
Subsets	Mostly CD8αα cells in liver and blood[101]	More IFN-γ and TNF-α than CD8αβ subset[101]

ABCB1: Multidrug resistance protein 1; APCs: Antigen presenting cells; CDRs: Complementarity-determining regions; IL: Interleukin; IFN-γ: Interferon-gamma; MAIT: Mucosal-associated invariant T cell; MR1: Major histocompatibility complex I-related molecule; PLZF: Promyelocytic leukemia zinc finger; T-bet: T-box transcription factor; TCR: T cells antigen receptor; t RORγt: Retinoic acid-related orphan receptor gamma t; TNF-α: Tumor necrosis factor-alpha.

Table 2 Mucosal-associated invariant T cell demographics and clinical implications

Feature	Demographics	Clinical implications
Frequency (based on percentage of CD3+ T cells)	Circulation, 0.1%-10%[11,61,81,131]; Intestine, 2%-20%[11,61,102,132]; Lung, 1%-10%[11,15,61,81]; Liver, 10%-40%[11,43,61,82,133]; Lymph nodes, < 1%[11,61]	Liver is most MAIT cell enriched tissue[61]; MAIT cells can react with microbial antigens and metabolites in portal circulation and in bile[133]
Hepatic distribution	Present in bile ducts, portal tracts, sinusoids[55,133]; Chemokine-directed migrations[77]; CCR6, CXCR6, integrin αEβ7 to bile ducts[77,133]; CXCR3, LFA-1, VLA-4 to sinusoids[77,133]	Nature of the liver disease may direct MAIT cell migration to key site of inflammation[77,133,134]
Age-related changes	Numbers in blood increase up to age 40 yr[135]; Numbers in blood decline after age 60 yr[135]; MAIT cell apoptosis increases with age[135]; Depletion nadir after age 80 yr[136]; Depletion may be faster in men than women[131]; Shift from CD8+ to CD4+ cells with aging[131,137]; May be less pro-inflammatory with aging[131]	Ethnic and environmental factors possible[135]; Uncertain effect on severity and outcome[136]; Consider in design of clinical investigations

LFA-1: Lymphocyte function-associated-1 protein; MAIT: Mucosal-associated invariant T cell; VLA-4: Very late antigen 4.

Table 3 Mucosal-associated invariant T cell activation and clinical implications

MAIT cell activation	Features	Clinical implications
MR1-dependent stimulation	Adaptive immune response[1,5]; Antigen-triggered MAIT cell activation[8,10,114]; MR1 undetectable before antigen exposure[140,144]; MR1 binds only small non-peptide molecules[147]; Riboflavin metabolites are main MR1 ligands[13]; Ribityllumazines are main riboflavin metabolites[13]; Bacterial and metabolic by-products can activate[9]; Drugs and drug metabolites can bind to MR1[153]	Antigens for presentation restricted[8,10]; Most microbes metabolize riboflavin[148]; Neo-antigens diversify MR1 repertoire[9]; Can develop effector memory cells[11]; Drugs can modulate MR1 signaling[153]; MR1 expression can be inhibited[155]
Modulation of MAIT cell response	Response biased by ligand and TCR β-chain[148]; Riboflavin metabolites differ among microbes[3]; CDR3β rearrangements alter antigen recognition[143]; IL-7 and non-microbial molecules can regulate[155]	Response differs among microbes[154]; TCR plasticity can affect response[143]; Local milieu modulates response[82,155]
Cytokine-dependent stimulation	Innate immune response[1,5]; Activates MAIT cells without TCR ligation[156]; Receptors for IL-7, IL-12, IL-18, IL-23, IFN-γ[81]; IL-18 is main MAIT cell activator[157,158]; IL-18 usually with other mediators[82,157,158]; IL-7, IL-18 produced by hepatocytes[81,158]; IL-1β, IL-18, IL-23 produced by monocytes[81,158]; IL-15 acts on MAIT cells directly and indirectly[158]; Bacteria elicit TLR8-induced cytokines[160]	Initiates rapid antimicrobial response[156]; Response affected by local mediators[81]; Effective against viral infections[32,33,159]; Anti-bacterial monocyte response[160]
Superantigen stimulation	Rapid powerful response to severe infection[138,163]; Bacterial exotoxins activate T cell populations[161]; Foregoes MR1 antigen activation[138,161]; Direct activation by binding to TCR Vβ[71,138,165]; Indirect activation by released IL-12, IL-18[71,138]; Generates robust release of cytokines[138]	MAIT cells are major responders[138]; May result in toxic shock[162]; Causes immune exhaustion[138,139,163]; May exacerbate autoimmune disease[168]; Induces pathogenic autoantibodies[166]

CDR3β: Complementarity-determining region 3-beta; IFN-γ: Interferon-gamma; IL: Interleukin; MAIT: Mucosal-associated invariant T; MR1: Major histocompatibility complex I-related molecule; TCR: T cell antigen receptor; TLR8: Toll-like receptor 8.

Table 4 Mucosal-associated invariant T cells in chronic hepatitis and clinical implications

Liver disease	MAIT cell features	Clinical implications
Chronic hepatitis B	Reduced frequency circulating MAIT cells[37,38]; Depletion increased by delta infection[45]; Depleted intrahepatic MAIT cells[38,39,45]; Less granzyme B, IFN-γ, IFN-α release[36,188]; Conjugated bilirubin linked to dysfunction[39]; Increased PD-1 and CTLA-4 on MAIT cells[36]; Exhaustion correlates with HBV DNA level[36]	Chronic activation and exhaustion[36,39]; Less antiviral action[36,39,188]; Increased MAIT cell death[99]; Presumed defective protective role[36]
Chronic hepatitis C	Reduced frequency circulating MAIT cells[41,42]; Depleted intrahepatic MAIT cell[43]; Increased histologic indices reflect depletion[43]; Less TCR-activation and IFN-γ production[40,43]; Increased PD-1 and CTLA-4 on MAIT cells[41]	Hyper-activation and exhaustion[40,41,43]; Increased MAIT cell death[43,61,99]; Antiviral therapy not restorative[40,42,43]; Presumed defective protective role[43]
Alcoholic hepatitis	Reduced frequency in blood and liver[46,47,133]; Decreased granzyme B and IL-17 production[46]; Circulating bacterial products[46,47]; Increased percentage PD-1+ MAIT cells[47]; Abundant circulating stimulatory cytokines[47]; Myofibroblasts stimulated and pro-fibrotic[63]	Hyper-activation and dysfunctional[46,47]; Immune exhaustion[46,47]; Impaired intestinal mucosal barrier[46,47]; Increased MAIT cell death[47]; Diminished anti-bacterial function[133]; Presumed defective protective role[46,47]
NAFLD	Circulating MAIT cell frequency decreased[51]; Circulating cells express PD-1 and CD69[51]; Increased intrahepatic MAIT cell frequency[51]; Frequency correlates with NAFLD score[51]; Decreased IFN-γ and TNF-α production[51]; IL-4 induced polarization to M2 macrophages[51]	Activated and immune exhausted[51]; Increased hepatic migration[51]; Recruited by inflammatory activity[51]; Reduced functionality[51]; Promotes anti-inflammatory milieu[51]; Presumed defective protective role[51]
Autoimmune hepatitis	Circulating MAIT cell frequency decreased[52,53]; Reduced granzyme B and IFN-γ secretion[52,53]; Variable intrahepatic frequency[52,53]; Increased IL-17A and HSC stimulation[52]; Increased expression of PD-1 and TIM-3[52]	Activated and immune exhausted[52,53]; Reduced functionality[52,53]; Pro-inflammatory cytokine milieu[52]; Progressive fibrosis[52]; Presumed active pathogenic role[52]

CTLA-4: Cytotoxic T lymphocyte antigen 4; HBV: Hepatitis B virus; HSC: Hepatic stellate cell; IFN-α: Interferon-alpha; IFN-γ: Interferon-gamma; MAIT: Mucosal-associated invariant T; NAFLD: Non-alcoholic fatty liver disease; PD-1: Programmed cell death 1; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; TIM-3: T cell immunoglobulin and mucin domain 3; TNF-α: Tumor necrosis factor-alpha.

Table 5 Mucosal-associated invariant T cells in cholestatic liver disease and decompensated cirrhosis

Liver disease	MAIT cell features	Clinical implications
PBC	Circulating MAIT cells decreased[54,55]; Intrahepatic MAIT cells variable[54,55]; Upregulated liver-homing CXCR6, CCR6[54]; Aberrant MAIT cell function[55]; Depletion associated with increased AP[55]; Low IFN-γ unable to impair HSC activation[55]; Preferential portal tract distribution[55]; Activation associated with increased ALT[54]; Cholic acid-induced hepatocyte IL-7[55]; IL-7-induced pro-inflammatory cytokines[55]; Limited expression of IL-7R and IL-18R[54]	Immune exhaustion[54,55]; Apoptosis-based depletion (AICD)[54,55]; Unable to prevent cholestasis[54,55]; Unable to inhibit hepatic fibrosis[55]; Defective barrier to gut-derived ligands[55]; Pro-inflammatory cytokine milieu[54,55]; UDCA improves but not restorative[54,55]; Presumed defective protective role[54,55]; Presumed active pathogenic role[54,55]
PSC	Circulating MAIT cell frequency reduced[57]; Intrahepatic MAIT cell frequency less[56]; CD69, CD56, PD-1, and CD39 expressed[57]; Impaired response to bacteria[57]; Abundant extrahepatic bile duct MAIT cells[57]	Activated and immune exhausted[57]; Depleted in circulation and liver tissue[56,57]; Less anti-bacterial protection[57]; Abundant migration to bile ducts[57]; Presumed defective protective role[57]
Decompensated cirrhosis	Circulating MAIT cell frequency reduced[58]; High expression of activation markers[58]; MAIT cell frequency increased in ascites[58]; Increased cytokines from peritoneal cells[58]; Increased granzyme B from peritoneal cells[58]; Increased frequency in SBP ascites[58]; Homing chemokine CXCR3 on MAIT cells[58]; Abundant CXCL10 ligand in ascites[58]	Activated and recruited to ascites[58]; Anti-microbial protective response[58]; Protective role of uncertain efficacy[58]

AICD: Activation-induced cell death; ALT: Serum alanine aminotransferase level; AP: Serum alkaline phosphatase level; HSC: Hepatic stellate cells; IFN-γ: Interferon-gamma; IL-7: Interleukin 7; IL-7R: Interleukin 7 receptor; IL-18R: Interleukin 18 receptor; MAIT: Mucosal-associated invariant T; PBC: Primary biliary cholangitis; PD-1: Programmed cell death 1; PSC: Primary sclerosing cholangitis; SBP: Spontaneous bacterial peritonitis; UDCA: Ursodeoxycholic acid.