Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2021; 27(25): 3705-3733
Published online Jul 7, 2021. doi: 10.3748/wjg.v27.i25.3705
Incorporating mucosal-associated invariant T cells into the pathogenesis of chronic liver disease
Albert J Czaja
Albert J Czaja, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, United States
Author contributions: Czaja AJ researched, designed, and wrote this article specifically for the World Journal of Gastroenterology; Czaja AJ constructed the 5 fully-referenced tables, created the figures.
Conflict-of-interest statement: The author has no conflict of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Albert J Czaja, FAASLD, AGAF, FACG, FACP, MD, Emeritus Professor, Department of Medicine, Mayo Clinic College of Medicine and Science, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States.
Received: December 19, 2020
Peer-review started: December 19, 2020
First decision: February 11, 2021
Revised: March 22, 2021
Accepted: June 15, 2021
Article in press: June 15, 2021
Published online: July 7, 2021

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.