Bacterial infections are a major cause of morbidity and mortality in patients with chronic viral hepatitis and liver cirrhosis. This clinical observation raises the question whether immune protection at the gut-liver axis is impaired. Mucosal associated invariant T (MAIT) cells are innate-like lymphocytes that are enriched at barrier sites such as the intestine, liver and lung and play a role in the host defense against bacterial infections. Their semi-invariant V7.2-J33 T cell receptor recognizes vitamin B metabolites from bacteria such as E. coli and they also respond to inflammatory cytokines such as IL-12 and IL-18. In this study we performed a comprehensive analysis of mucosal activated invariant T cells (MAIT cells) in both blood and liver in chronic HCV infection. MAIT cells were reduced in numbers in HCV-induced liver inflammation and their intrahepatic frequency correlated inversely with liver inflammation and fibrosis. We suggest that MAIT cells are recruited from the blood to the liver in chronic HCV infection where they are activated by inflammatory cytokines and undergo activation-induced cell death. This is consistent with our observation of a selective loss of CD8+ MAIT cells upon in vitro stimulation with either IL-12/IL-18 or E. coli/IL-15. It is also consistent with the increase in the frequency of MAIT cells in the liver along with the resolution of liver inflammation by week four of antiviral therapy. As regards to effector function, MAIT cells of chronic HCV patients produced IFN-g in response to IL-12/IL-18 stimulation. MAIT cells also exerted cytotoxic effector functions as indicated by increased expression of the degranulation marker CD107a. In contrast, MAIT cell function in response to E. coli stimulation was impaired in patients with chronic HCV infection, which may impact MAIT-cell dependent protection against bacterial infections in advanced liver disease.
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