Anita Schuch1, Britta Franziska Zecher2, Philipp Andreas Müller2, Margareta P Correia3, Franziska Daul1, Charlotte Rennert2, Catrin Tauber1, Karolin Schlitt2, Tobias Boettler2, Christoph Neumann-Haefelin2, Hartmut Hengel4, Hanspeter Pircher5, Adelheid Cerwenka6, Robert Thimme2, Maike Hofmann7. 1. Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany; Faculty of Biology, University of Freiburg, Schänzlestraße 1, Freiburg 79104, Germany. 2. Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany. 3. Innate Immunity Group, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. 4. Institute of Virology, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hermann-Herder-Straße 11, Freiburg 79104, Germany. 5. Institute for Immunology, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hermann-Herder-Straße 11, Freiburg 79104, Germany. 6. Innate Immunity Group, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Immunobiochemistry, University of Heidelberg, Medical Faculty Mannheim, Ludolf-Krehl-Strasse 13-17, Mannheim 68167, Germany. 7. Department of Medicine II, University Hospital Freiburg - Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, Freiburg 79106, Germany. Electronic address: maike.hofmann@uniklinik-freiburg.de.
Abstract
BACKGROUND & AIMS: Phenotypic and functional natural killer (NK)-cell alterations are well described in chronic hepatitis B virus (cHBV) infection. However, it is largely unknown whether these alterations result from general effects on the overall NK-cell population or the emergence of distinct NK-cell subsets. Human cytomegalovirus (HCMV) is common in cHBV and is associated with the emergence of memory-like NK cells. We aimed to assess the impact of these cells on cHBV infection. METHODS: To assess the impact of memory-like NK cells on phenotypic and functional alterations in cHBV infection, we performed in-depth analyses of circulating NK cells in 52 patients with cHBV, 45 with chronic hepatitis C virus infection and 50 healthy donors, with respect to their HCMV serostatus. RESULTS: In patients with cHBV/HCMV+, FcεRIγ- memory-like NK cells were present in higher frequencies and with higher prevalence than in healthy donors with HCMV+. This pronounced HCMV-associated memory-like NK-cell expansion could be identified as key determinant of the NK-cell response in cHBV infection. Furthermore, we observed that memory-like NK cells consist of epigenetically distinct subsets and exhibit key metabolic characteristics of long-living cells. Despite ongoing chronic infection, the phenotype of memory-like NK cells was conserved in patients with cHBV/HCMV+. Functional characteristics of memory-like NK cells also remained largely unaffected by cHBV infection with the exception of an increased degranulation capacity in response to CD16 stimulation that was, however, detectable in both memory-like and conventional NK cells. CONCLUSIONS: The emergence of HCMV-associated memory-like NK cells shapes the overall NK-cell response in cHBV infection and contributes to a general shift towards CD16-mediated effector functions. Therefore, HCMV coinfection needs to be considered in the design of immunotherapeutic approaches that target NK cells in cHBV. LAY SUMMARY: In chronic hepatitis B virus infection, natural killer (NK)-cell phenotype and function is altered. In this study, we demonstrate that these changes are linked to the emergence of a distinct NK-cell subset, namely memory-like NK cells. The emergence of these memory-like NK cells is associated with coinfection of human cytomegalovirus that affects the majority of patients with chronic hepatitis B.
BACKGROUND & AIMS: Phenotypic and functional natural killer (NK)-cell alterations are well described in chronic hepatitis B virus (cHBV) infection. However, it is largely unknown whether these alterations result from general effects on the overall NK-cell population or the emergence of distinct NK-cell subsets. Human cytomegalovirus (HCMV) is common in cHBV and is associated with the emergence of memory-like NK cells. We aimed to assess the impact of these cells on cHBV infection. METHODS: To assess the impact of memory-like NK cells on phenotypic and functional alterations in cHBV infection, we performed in-depth analyses of circulating NK cells in 52 patients with cHBV, 45 with chronic hepatitis C virus infection and 50 healthy donors, with respect to their HCMV serostatus. RESULTS: In patients with cHBV/HCMV+, FcεRIγ- memory-like NK cells were present in higher frequencies and with higher prevalence than in healthy donors with HCMV+. This pronounced HCMV-associated memory-like NK-cell expansion could be identified as key determinant of the NK-cell response in cHBV infection. Furthermore, we observed that memory-like NK cells consist of epigenetically distinct subsets and exhibit key metabolic characteristics of long-living cells. Despite ongoing chronic infection, the phenotype of memory-like NK cells was conserved in patients with cHBV/HCMV+. Functional characteristics of memory-like NK cells also remained largely unaffected by cHBV infection with the exception of an increased degranulation capacity in response to CD16 stimulation that was, however, detectable in both memory-like and conventional NK cells. CONCLUSIONS: The emergence of HCMV-associated memory-like NK cells shapes the overall NK-cell response in cHBV infection and contributes to a general shift towards CD16-mediated effector functions. Therefore, HCMV coinfection needs to be considered in the design of immunotherapeutic approaches that target NK cells in cHBV. LAY SUMMARY: In chronic hepatitis B virus infection, natural killer (NK)-cell phenotype and function is altered. In this study, we demonstrate that these changes are linked to the emergence of a distinct NK-cell subset, namely memory-like NK cells. The emergence of these memory-like NK cells is associated with coinfection of human cytomegalovirus that affects the majority of patients with chronic hepatitis B.
Authors: Guang He Ran; Yu Qing Lin; Lei Tian; Tao Zhang; Dong Mei Yan; Jian Hua Yu; You Cai Deng Journal: Signal Transduct Target Ther Date: 2022-06-29