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MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation
Open accessAbstract
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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“The crucial role 446 of MAIT cells as liver sentinels against bacteria is suggested by the effect of their 447 dysfunction in alcoholic liver disease, which increases greatly the susceptibility of these 448 patients to liver infections(90, 91).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [91]
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“Although the role of MAIT cells in the liver is evolving, experimental evidence clearly supports their profibrogenic activity in the chronically injured liver.99,100”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [100]
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Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 1×
“The severe decline of MAIT cells observed in both peripheral blood and liver tissue of AILD patients probably results from chronic activation and cellular exhaustion, which is commonly characterized by a hierarchical loss of effector function, followed by cell death.((30)) T cell exhaustion arises from chronic exposur…”
BackgroundInterleukin-12 and the regulation of innate resistance and adaptive immunity
Trinchieri, G. (2003) · Nature reviews. Immunology · doi:10.1038/nri1001 · Cited by 4,007
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Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function
Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive, D. J. D., Suresh, M., Altman, J. D., & Ahmed, R. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2205 · Cited by 1,978
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MR1 presents microbial vitamin B metabolites to MAIT cells
Kjer-Nielsen, L., Patel, O., Corbett, A. J., Le Nours, J., Meehan, B., Liu, L., Bhati, M., Chen, Z., Kostenko, L., Reantragoon, R., et al. (2012) · Nature · doi:10.1038/nature11605 · Cited by 1,351
The IL-23/IL-17 axis in inflammation
Iwakura, Y. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28508 · Cited by 1,068
Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17–secreting T cells
Dusséaux, M., Martin, E., Serriari, N., Péguillet, I., Prémel, V., Louis, D., Milder, M., Bourhis, L. L., Soudais, C., Treiner, E., et al. (2010) · Blood · doi:10.1182/blood-2010-08-303339 · Cited by 1,045
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Hammerich, L., & Tacke, F. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00807-x · Cited by 803
Peiseler, M., Schwabe, R., Hampe, J., Kubes, P., Heikenwälder, M., & Tacke, F. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.06.012 · Cited by 564
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An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH
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Metadata
- 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
- Venue
- Hepatology
- Published
- 2018-07
- Volume
- 68
- Issue
- 1
- Pages
- 172-186
- ISSN
- 0270-9139 (ISSN-L)
- 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
- 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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