NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection

TY - JOUR

T1 - NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection

AU - Schuch, Anita

AU - Zecher, Britta Franziska

AU - Müller, Philipp Andreas

AU - Correia, Margareta P

AU - Daul, Franziska

AU - Rennert, Charlotte

AU - Tauber, Catrin

AU - Schlitt, Karolin

AU - Boettler, Tobias

AU - Neumann-Haefelin, Christoph

AU - Hengel, Hartmut

AU - Pircher, Hanspeter

AU - Cerwenka, Adelheid

AU - Thimme, Robert

AU - Hofmann, Maike

N1 - Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.jhep.2018.10.006

DO - 10.1016/j.jhep.2018.10.006

M3 - SCORING: Journal article

C2 - 30342116

VL - 70

SP - 351

EP - 360

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 3

ER -