• Chronic hepatitis C virus infection irreversibly impacts human natural killer cell repertoire diversity.

      Strunz, Benedikt; Hengst, Julia; Deterding, Katja; Manns, Michael P; Cornberg, Markus; Ljunggren, Hans-Gustaf; Wedemeyer, Heiner; Björkström, Niklas K; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2018-06-11)
      Diversity is a central requirement for the immune system's capacity to adequately clear a variety of different infections. As such, natural killer (NK) cells represent a highly diverse population of innate lymphocytes important in the early response against viruses. Yet, the extent to which a chronic pathogen affects NK cell diversity is largely unknown. Here we study NK cell functional diversification in chronic hepatitis C virus (HCV) infection. High-dimensional flow cytometer assays combined with stochastic neighbor embedding analysis reveal that chronic HCV infection induces functional imprinting on human NK cells that is largely irreversible and persists long after successful interventional clearance of the virus. Furthermore, HCV infection increases inter-individual, but decreases intra-individual, NK cell diversity. Taken together, our results provide insights into how the history of infections affects human NK cell diversity.
    • Irreversible impact of chronic hepatitis C virus infection on human natural killer cell diversity.

      Strunz, Benedikt; Hengst, Julia; Wedemeyer, Heiner; Björkström, Niklas K; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. (Shared Science org, 2018-07-25)
      Diversity is crucial for the immune system to efficiently combat infections. Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to the control of viral infections. NK cells were for long thought to be a homogeneous population of cells. However, recent work has instead revealed NK cells to represent a highly diverse population of immune cells where a vast number of subpopulations with distinct characteristics exist across tissues. However, the degree to which a chronic viral infection affects NK cell diversity remains elusive. Hepatitis C virus (HCV) is effective in establishing chronic infection in humans. During the last years, new direct-acting antiviral drugs (DAA) have revolutionized treatment of chronic hepatitis C, enabling rapid cure in the majority of patients. This allows us to study the influence of a chronic viral infection and its subsequent elimination on the NK cell compartment with a focus on NK cell diversity. In our recent study (Nat Commun, 9:2275), we show that chronic HCV infection irreversibly impacts human NK cell repertoire diversity.
    • MAIT cells are enriched and highly functional in ascites of patients with decompensated liver cirrhosis.

      Niehaus, Christian E; Strunz, Benedikt; Cornillet, Martin; Falk, Christine S; Schnieders, Ansgar; Maasoumy, Benjamin; Hardtke, Svenja; Manns, Michael P; Rm Kraft, Anke; Björkström, Niklas K; et al. (Wiley Online Open, 2020-02-03)
      Patients with advanced liver cirrhosis have an increased susceptibility to infections. As part of the cirrhosis-associated immune dysfunction, mucosal associated invariant T (MAIT) cells, that have the capacity to respond towards bacteria, are severely diminished in circulation and liver tissue. However, MAIT cell presence and function in the peritoneal cavity, a common anatomical site for infections in cirrhosis, remain elusive. To study this, matched peripheral blood and ascites fluid were collected from 35 patients with decompensated cirrhosis, with or without spontaneous bacterial peritonitis (SBP). MAIT cell phenotype and function were analyzed using high-dimensional flow cytometry and obtained data was compared to blood samples of healthy controls (n=24) and patients with compensated cirrhosis (n=11). We found circulating MAIT cells to be severely decreased in cirrhotic patients as compared to controls. In contrast, in ascites fluid, MAIT cells were significantly increased together with CD14+ CD16+ monocytes, ILCs, and NK cells. This was paralleled by elevated levels of several pro-inflammatory cytokines and chemokines in ascites fluid as compared to plasma. Peritoneal MAIT cells displayed an activated tissue-resident phenotype and this was corroborated by increased functional responses following stimulation with E. coli or lL-12 + IL-18 as compared to circulating MAIT cells. During SBP, peritoneal MAIT cell frequencies increased most among all major immune cell subsets, suggestive of active homing of MAIT cells to the site of infection. CONCLUSIONS: Despite severely diminished MAIT cell numbers and impaired phenotype in circulation, peritoneal MAIT cells remain abundant, activated, and highly functional in decompensated cirrhosis and are further enriched in SBP. This suggests that peritoneal MAIT cells could be of interest for immune intervention strategies in patients with decompensated liver cirrhosis and SBP.