Mucosal- associated invariant T (MAIT) cells are significantly decreased and exhausted in patients with autoimmune liver disease, but promote primary hepatic stellate cell (HSC) activation

MAIT cells are innate-like T cells that are particularly enriched in the liver and alterations in MAIT cell frequency/function have been linked with autoimmune conditions. Autoimmune liver diseases (AILD) are characterised by... [ view full abstract ]

MAIT cells are innate-like T cells that are particularly enriched in the liver and alterations in MAIT cell frequency/function have been linked with autoimmune conditions. Autoimmune liver diseases (AILD) are characterised by immune-mediated liver damage, leading to liver fibrosis and cirrhosis. In this study, we addressed the question whether MAIT cells are altered in patients with AILD and if MAIT cells can promote liver fibrosis through HSC activation.

MAIT cells were stimulated with PMA/Ionomycin, or with IL-1β, IL-12 and IL-18 for 16-72 hours. Intracellular cytokine expression was measured by flow cytometry. Moreover, proliferation of HSCs co-cultured with MAIT cells was assessed by BrdU assay and gene expression was analysed by quantitative real-time PCR. 

MAIT cells were significantly decreased in peripheral blood and liver tissue of patients with AILD. This decrease inversely correlated with the fibrosis stage. Moreover, MAIT cells from patients were exhausted, shown by impaired IFNγ production and significantly higher ex vivo expression of activation and exhaustion markers, such as CD38, HLA-DR and CTLA-4, in MAIT cells from AILD patients compared to HC. MAIT cells exhaustion could be driven by repetitive stimulation with IL-12 + IL-18, resulting in decreasing IFNγ and increasing exhaustion marker expression. Notably, repetitive stimulation with IL-12 stimulated IL-17A expression, a pro-fibrogenic cytokine in MAIT cells. Moreover, MAIT cells were able to induce an activated, pro-fibrogenic phenotype in vitro.

Thus, MAIT cells might contribute to the development of fibrosis in AILD and represent a novel therapeutic target.