Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 153; no. 5; pp. 1392 - 1403.e2
• Main Authors: Bolte, Fabian J., O’Keefe, Ashley C., Webb, Lauren M., Serti, Elisavet, Rivera, Elenita, Liang, T. Jake, Ghany, Marc, Rehermann, Barbara
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2017
• Subjects: Antiviral Agents - therapeutic use; Biopsy; Carbamates - therapeutic use; Case-Control Studies; Cirrhosis; Cytokines - immunology; Drug Combinations; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - virology; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Humans; Immune Regulation; Leukocyte Count; Liver - drug effects; Liver - immunology; Liver - virology; Lymphocyte Activation; Monocytes - immunology; Mucosal-Associated Invariant T Cells - drug effects; Mucosal-Associated Invariant T Cells - immunology; Mucosal-Associated Invariant T Cells - virology; Paracrine Communication; Phenotype; Response to Treatment; Sofosbuvir - therapeutic use; Sustained Virologic Response; SVR; Time Factors; Treatment Outcome; PBS; TCR; IQR; PBMC; SVR; Response to Treatment; Cirrhosis; SD; IFN-γ; TNF-α; FBS; Immune Regulation; EMA; FIB-4; HCV; MAIT
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2017.07.043

Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal-associated invariant T (MAIT) cells are enriched in the liver as compared with the blood, respond to intra-hepatic cytokines, and (via the semi-invariant T-cell receptor) to bacteria translocated from the gut. Little is known about the role of MAIT cells in livers of patients with chronic hepatitis C virus (HCV) infection and their fate after antiviral therapy.
We collected blood samples from 42 patients with chronic HCV infection who achieved a sustained virologic response after 12 weeks of treatment with sofosbuvir and velpatasvir. Mononuclear cells were isolated from blood before treatment, at weeks 4 and 12 during treatment, and 24 weeks after the end of treatment. Liver biopsies were collected from 37 of the patients prior to and at week 4 of treatment. Mononuclear cells from 56 blood donors and 10 livers that were not suitable for transplantation were used as controls. Liver samples were assessed histologically for inflammation and fibrosis. Mononuclear cells from liver and blood were studied by flow cytometry and analyzed for responses to cytokine and bacterial stimulation.
The frequency of MAIT cells among T cells was significantly lower in blood and liver samples of patients with HCV infection than of controls (median, 1.31% vs 2.32% for blood samples, P = .0048; and median, 4.34% vs 13.40% for liver samples, P = .001). There was an inverse correlation between the frequency of MAIT cells in the liver and histologically determined levels of liver inflammation (r = -.5437, P = .0006) and fibrosis (r = -.5829, P = .0002). MAIT cells from the liver had higher levels of activation and cytotoxicity than MAIT cells from blood (P < .0001). Production of interferon gamma by MAIT cells was dependent on monocyte-derived interleukin 18, and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared with controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy.
In analyses of paired blood and liver samples from patients with chronic HCV infection before, during, and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation.