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

Schuch, Anita; Zecher, Britta Franziska; Müller, Philipp Andreas; Correia, Margareta P.; Daul, Franziska; Rennert, Charlotte; Tauber, Catrin; Schlitt, Karolin; Böettler, Tobias; Hengel, Hartmut; Pircher, Hanspeter; Cerwenka, Adelheid; Thimme, Robert; Hofmann, Maike

doi:10.1016/j.jhep.2018.10.006

Cited by 31 publications

(40 citation statements)

References 46 publications

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“…Compared with conventional FcεRIγ+CD56 dim NK cells, this NK subpopulation displays different metabolic properties, including a higher fraction of functional, polarized mitochondria, and a stable epigenetic signature, along with increased CD16-mediated degranulation potential, which skews the whole NK cell population toward a higher CD16 sensitivity with enhanced ADCC. These data show the mutual influence of HBV- and HCMV-persisting infections on the NK cell repertoire, which significantly affects the immune response to chronic HBV infection, and point to the usefulness of HCMV co-infection evaluation in the application of immunotherapeutic approaches targeting NK cells for an HBV cure [49]. Moreover, KLRG1 upregulation has been detected on circulating and intrahepatic memory-like FcεRIγ-CD56 dim NK cells from CHB patients, which characterizes a subset with anti-fibrotic function exerted by a strong TRAIL-mediated induction of hepatic stellate cell (HSC) apoptosis.…”

Section: Nk Cells In Hbv Infectionmentioning

confidence: 99%

“…Some conflicting results have been reported due to the wide spectrum of different clinical conditions characterizing the natural history of HBV infection [3]. As compared with healthy donors, a high expression of some activation/proliferation markers and death ligands (TRAIL) was observed both on peripheral and intrahepatic NK cells from chronic patients [47,48,49], particularly in the active hepatitis stage [50,51,52,53,54,55,56]. Intrahepatic NKG2D up-regulation was proposed to mediate NK activation and liver inflammation, which was particularly amplified in patients with acute-on-chronic liver failure (ACLF) [57].…”

Section: Nk Cells In Hbv Infectionmentioning

confidence: 99%

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The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

Fisicaro

Rossi

Vecchi

et al. 2019

IJMS

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Immune modulatory therapies are widely believed to represent potential therapeutic strategies for chronic hepatitis B infection (CHB). Among the cellular targets for immune interventions, Natural Killer (NK) cells represent possible candidates because they have a key role in anti-viral control by producing cytokines and by exerting cytotoxic functions against virus-infected cells. However, in patients with chronic hepatitis B, NK cells have been described to be more pathogenic than protective with preserved cytolytic activity but with a poor capacity to produce anti-viral cytokines. In addition, NK cells can exert a regulatory activity and possibly suppress adaptive immune responses in the setting of persistent viral infections. Consequently, a potential drawback of NK-cell targeted modulatory interventions is that they can potentiate the suppressive NK cell effect on virus-specific T cells, which further causes impairment of exhausted anti-viral T cell functions. Thus, clinically useful NK-cell modulatory strategies should be not only suited to improve positive anti-viral NK cell functions but also to abrogate T cell suppression by NK cell-mediated T cell killing. This review outlines the main NK cell features with a particular focus on CHB infection. It describes different mechanisms involved in NK-T cell interplay as well as how NK cells can have positive anti-viral effector functions and negative suppressive effects on T cells activity. This review discusses how modulation of their balance can have potential therapeutic implications.

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Section: Nk Cells In Hbv Infectionmentioning

confidence: 99%

Section: Nk Cells In Hbv Infectionmentioning

confidence: 99%

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

Fisicaro

Rossi

Vecchi

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…Similarly, a study showed that NK cells with a less mature phenotype, NKG2A + CD57 - NKG2C - (CD57 + is a marker of terminal differentiation), were associated with protection from leukemia relapse and improved OS [92]. This is also contrary to the conventional knowledge that mature and memory-like NKG2A − selfKIR + CD57 + NKG2C + NK cells generated by cytokine stimulation or CMV infection are more efficacious [93,94,95,96,97,98]. Although a unifying explanation for these seemingly contradictory findings is not yet available, recent observations suggest that the phenotype of NK cells determines the function, and CD56 bright or CD56 superbright NK cells may not only differentiate into mature cytotoxic NK cells, but also secrete enough cytokines to overcome the immunosuppressive tumor microenvironment [99].…”

Section: Strategies To Enhance the Effect Of Nk Cell Therapymentioning

confidence: 99%

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors

Lee

Kwack

et al. 2019

Cancers

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In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.

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“…[ 43 , 50 ] In short, NK cells display a functional dichotomy in CHB patients, characterized by impaired noncytolytic antiviral capacity such as IFN-γ production and enhanced or preserved cytotoxic function such as the degranulation capacity. [ 51 , 52 ] Furthermore, HIV-infected individuals exhibit significantly enhanced degranulation and IFN-γ production but no difference in IL-10 level compared with HCs. Our results are consistent with previous reports, [ 18 , 53 ] suggesting that NK cell functions are greatly enhanced in individuals with PHI relative to HCs.…”

Section: Discussionmentioning

confidence: 99%

NKG2C+ natural killer cell function improves the control of HBV replication in individuals with acute HIV infection coinfected with HBV

Song

et al. 2020

Medicine

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Individuals infected with hepatitis B virus (HBV) are often coinfected with human immunodeficiency virus (HIV). However, individuals with chronic HBV infection living with acute HIV infection have a significantly lower HBV viral load, along with higher HBeAg and HBsAg loss than HBV-infected individuals alone. Here, we investigated the possible role of natural killer cells (NK cell) function in this progressive course to explore the relationship between phenotypic/functional changes in NK cells during acute HIV infection and HBV clearance in patients with HIV/HBV coinfection. Peripheral blood NK cells from 38 patients with primary HIV infection, including 20 with untreated HIV infection and 18 treatment-naïve patients with HIV/HBV coinfection and 16 patients with chronic HBV infection, were enrolled in this study. We found that the HIV/HBV-coinfected individuals had higher levels of NK cells than the HBV-infected individuals, due to expansion of the CD56 neg NK cell population. The proportion of NK cells in CD56 dim and CD56 bri NK subsets was not found significant difference between HIV/HBV-coinfected and HBV-infected individuals. However, NKG2C levels on NK cells and subsets were significantly higher in HIV/HBV-coinfected individuals than in HBV-infected individuals, whereas NKG2A levels were unaffected or decreased. In addition, the levels of degranulation CD107a, cytotoxicity and IFN-γ production of NK cells were increased in HIV/HBV-coinfected individuals than in HBV-infected individuals. The level of IL-10 production of NK cells was decreased in HIV/HBV-coinfected individuals than in HBV-infected individuals. Furthermore, the level of HBV-DNA was inversely correlated with the proportion of NKG2C + and NKG2C + NKG2A − NK cells, while positively correlated with the proportion of NKG2A + and NKG2C - NKG2A + NK cells. IFN-γ production was inversely correlated with levels of HBV-DNA, but the CD107a expression and IL-10 production of NK cells were not correlated with HBV-DNA levels. These results demonstrate that the upregulation of NKG2C expression, but not of NKG2A expression on the surface of NK cells increases cytolytic capacity and the amounts of cytokines produced and may play a crucial role in HBV clearance during HIV/HBV-coinfection.

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

Cited by 31 publications

References 46 publications

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

The Good and the Bad of Natural Killer Cells in Virus Control: Perspective for Anti-HBV Therapy

Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors

NKG2C+ natural killer cell function improves the control of HBV replication in individuals with acute HIV infection coinfected with HBV

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