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

Abstract

Mucosal-associated invariant T (MAIT) cells have been described in liver and non-liver diseases, and they have been ascribed antimicrobial, immune regulatory, protective, and pathogenic roles. The goals of this review are to describe their biological properties, indicate their involvement in chronic liver disease, and encourage investigations that clarify their actions and therapeutic implications. English abstracts were identified in PubMed by multiple search terms, and bibliographies were developed. MAIT cells are activated by restricted non-peptides of limited diversity and by multiple inflammatory cytokines. Diverse pro-inflammatory, anti-inflammatory, and immune regulatory cytokines are released; infected cells are eliminated; and memory cells emerge. Circulating MAIT cells are hyper-activated, immune exhausted, dysfunctional, and depleted in chronic liver disease. This phenotype lacks disease-specificity, and it does not predict the biological effects. MAIT cells have presumed protective actions in chronic viral hepatitis, alcoholic hepatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, and decompensated cirrhosis. They have pathogenic and pro-fibrotic actions in autoimmune hepatitis and mixed actions in primary biliary cholangitis. Local factors in the hepatic microenvironment (cytokines, bile acids, gut-derived bacterial antigens, and metabolic by-products) may modulate their response in individual diseases. Investigational manipulations of function are warranted to establish an association with disease severity and outcome. In conclusion, MAIT cells constitute a disease-nonspecific, immune response to chronic liver inflammation and infection. Their pathological role has been deduced from their deficiencies during active liver disease, and future investigations must clarify this role, link it to outcome, and explore therapeutic interventions.

Keywords: Innate-like lymphocytes; Antimicrobial; Immune regulatory; Pathogenic; Mucosal-associated invariant T cell

Core Tip: Circulating mucosal-associated invariant T cells are depleted in chronic liver disease, and they have a disease-nonspecific, hyper-activated, immune exhausted, and dysfunctional phenotype. Antimicrobial, immune regulatory, pro-inflammatory, and anti-inflammatory actions are established biological functions of these innate-like lymphocytes, and each function has been invoked to understand the pathogenesis of chronic hepatitis and cholestatic liver disease. Future investigations must establish their pathological role in each form of chronic liver disease, determine the factors that direct function in the hepatic microenvironment, associate deficient functionality with disease severity and outcome, and explore therapeutic manipulations.