Background & Aims Chronic hepatitis affects phenotypes of innate and adaptive immune cells. Mucosal associated invariant T (MAIT) cells are enriched in the liver as compared to 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. Methods 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. Results 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 (IFNG) by MAIT cells was dependent on monocyte-derived interleukin 18 (IL18), and was reduced in patients with HCV infection in response to T-cell receptor-mediated but not cytokine-mediated stimulation, as compared to 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. Conclusions 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.

Background All vertebrate peripheral nerves connect the central nervous system (CNS) with targets in the periphery and are composed of axons, layers of ensheathing glia and connective tissue. Although the structure of these conduits is well established, very little is known about the origin and developmental roles of some of their elements. One understudied component, the perineurium, ensheaths nerve fascicles and is a component of the blood-nerve-barrier. In zebrafish, the motor nerve perineurium is composed of CNS-derived nkx2.2a+ perineurial glia, which establish the motor exit point (MEP) during development. To determine if mouse perineurial cells also originate within the CNS and perform a similar function, we created a Nkx2.2:EGFP transgenic reporter line. Results In conjunction with RNA expression analysis and antibody labeling, we observed Nkx2.2+ cells along peripheral motor nerves at all stages of development and in adult tissue. Additionally, in mice lacking Nkx2.2, we demonstrate that Nkx2.2+ perineurial glia are essential for motor nerve development and Schwann cell differentiation. Conclusions Our studies reveal that a subset of mouse perineurial cells are CNS-derived, express Nkx2.2, and are essential for motor nerve development. This work highlights an under-appreciated but essential contribution of CNS-derived cells to the development of the mammalian peripheral nervous system (PNS).

NCT01888900 and NCT00718172.