Cited by 183Liver Diseases and ImmunityLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

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MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation

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Böttcher, Katrin, Rombouts, Krista, Saffioti, Francesca, Roccarina, Davide, Rosselli, Matteo, Hall, Andrew, Luong, TuVinh, Tsochatzis, Emmanuel A., Thorburn, Douglas, Pinzani, Massimo·2018·Hepatology

DOI 10.1002/hep.29782

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Abstract

Autoimmune liver diseases (AILDs) are chronic liver pathologies characterized by fibrosis and cirrhosis due to immune-mediated liver damage. In this study, we addressed the question whether mucosal-associated invariant T (MAIT) cells, innate-like T cells, are functionally altered in patients with AILD and whether MAIT cells can promote liver fibrosis through activation of hepatic stellate cells (HSCs). We analyzed the phenotype and function of MAIT cells from AILD patients and healthy controls by multicolor flow cytometry and investigated the interaction between human MAIT cells and primary human hepatic stellate cells (hHSCs). We show that MAIT cells are significantly decreased in peripheral blood and liver tissue of patients with AILD. Notably, MAIT cell frequency tended to decrease with increasing fibrosis stage. MAIT cells from AILD patients showed signs of exhaustion, such as impaired interferon-γ (IFN-γ) production and high ex vivo expression of the activation and exhaustion markers CD38, HLA-DR, and CTLA-4. Mechanistically, this exhausted state could be induced by repetitive stimulation of MAIT cells with the cytokines interleukin (IL)-12 and IL-18, leading to decreased IFN-γ and increased exhaustion marker expression. Of note, repetitive stimulation with IL-12 further resulted in expression of the profibrogenic cytokine IL-17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, proinflammatory and profibrogenic phenotype in hHSCs in vitro that was partly mediated by IL-17. CONCLUSION: Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, profibrogenic phenotype and can contribute to the development of HSC-mediated liver fibrosis. These findings reveal a cellular and molecular pathway for fibrosis development in AILD that could be exploited for antifibrotic therapy. (Hepatology 2018;68:172-186).

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Authors: Böttcher, K., Rombouts, K., Saffioti, F., Roccarina, D., Rosselli, M., Hall, A., Luong, T., Tsochatzis, E. A., Thorburn, D., & Pinzani, M.
Affiliations: The Royal Free Hospital (GB)
University of Messina (IT)
Corresponding author: Böttcher, Katrin
ORCID: Böttcher, Katrin
Rombouts, Krista
Saffioti, Francesca
Roccarina, Davide
Hall, Andrew
Tsochatzis, Emmanuel A.
Thorburn, Douglas
Pinzani, Massimo
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2018-07
Volume: 68
Issue: 1
Pages: 172-186
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.29782
OpenAlex: W2783230342
Cited by: 183
References: 50
Citations by year: 2026: 12 · 2025: 17 · 2024: 24 · 2023: 24 · 2022: 20 · 2021: 26 · 2020: 35 · 2019: 16 · 2018: 8
FWCI: 13.32
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm)
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: National Institute for Health and Care Research
University College London Hospitals NHS Foundation Trust
European Association for the Study of the Liver
Innovate UK
Royal Free Charity
Topics: Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: mucosal-associated invariant T cells, autoimmune liver disease, liver fibrosis, hepatic stellate cell activation, T cell exhaustion, interferon-gamma, IL-12, IL-18, IL-17A, antifibrotic therapy, chronic liver disease
MeSH terms: Mucosal-Associated Invariant T Cells, Adult, Aged, Aged, 80 and over, Autoimmune Diseases, Female, Humans, Interleukins, Liver Cirrhosis, Lymphocyte Activation, Male, Middle Aged, Phenotype, Case-Control Studies, Cell Death, Hepatic Stellate Cells, Young Adult

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MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation

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