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

Böttcher, K; rombouts, K; Saffioti, F; Roccarina, D; Rosselli, M; Hall, A; Luong, T; ... Pinzani, M; + view all (2018) MAIT cells are chronically activated in patients with autoimmune liver disease and promote pro-fibrogenic hepatic stellate cell activation. Hepatology , 68 (1) pp. 172-186. 10.1002/hep.29782. Green open access

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Abstract

Autoimmune liver diseases (AILD) are chronic liver pathologies characterised 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. We analysed the phenotype and function of MAIT cells from AILD patients and healthy controls by multi-colour 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 IFNγ 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 IL-12 and IL-18, leading to decreased IFNγ and increased exhaustion marker expression. Of note, repetitive stimulation with IL-12 further resulted in expression of the pro-fibrogenic cytokine IL-17A by otherwise exhausted MAIT cells. Accordingly, MAIT cells from both healthy controls and AILD patients were able to induce an activated, pro-inflammatory and pro-fibrogenic phenotype in hHSCs in vitro, which was partly mediated by IL-17. Conclusion: Our data provide evidence that MAIT cells in AILD patients have evolved towards an exhausted, pro-fibrogenic 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 anti-fibrotic therapy.

Type: Article
Title: MAIT cells are chronically activated in patients with autoimmune liver disease and promote pro-fibrogenic hepatic stellate cell activation
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/hep.29782
Publisher version: http://dx.doi.org/10.1002/hep.29782
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: primary sclerosing cholangitis (PSC); primary biliary cholangitis (PBC); autoimmune hepatitis (AIH); liver fibrosis; non-alcoholic steatohepatitis (NASH)
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Internal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10041550
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