ADCC-Mediated CD56dim NK Cell Responses Are Associated with Early HBsAg Clearance in Acute HBV Infection

Abstract

BackgroundHepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection.MethodsBecause immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines.ResultsMultivariate analysis revealed selective perturbation of the CD56dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation.ConclusionThe cytolytic CD56dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.

Natural killer cells play an important role in virus infection control: Antiviral mechanism, subset expansion and clinical application

“…Interestingly, the cytolytic CD56dim NK-cell subset in the peripheral blood is selectively activated and expands in acute HBV infection, displaying distinct phenotypic and functional profiles associated with efficient and early control of HBV. This implicates NK cell cytolytic responses in the early containment and resolution of HBV infection [ 60 , 96 ]. Furthermore, early clearance of hepatitis B surface antigen (HBsAg) can be predicted by a distinct CD56dim NK cells phenotypic profile [ 60 , 96 ].…”

“…This implicates NK cell cytolytic responses in the early containment and resolution of HBV infection [ 60 , 96 ]. Furthermore, early clearance of hepatitis B surface antigen (HBsAg) can be predicted by a distinct CD56dim NK cells phenotypic profile [ 60 , 96 ]. In HBV-infected patients, memory-like FcεRIγ-/CD56dim NK cells with higher NKG2C and lower NKG2A expression undergo increased cytokine responses and CD16-mediated ADCC compared to conventional CD56dim NK cells following exposure to HCMV [ 97 ].…”

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

“…Functional analysis revealed that elevated antibody-mediated cytotoxicity degranulation can represent a key mechanism in early clearance. On the other hand, higher cytokine production was detected in the case of later clearance, which suggests that ADCC-mediated NK cell killing is more effective than non-cytopathic mechanisms in the early control of acute HBV infection [46].…”

Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

“…Natural killer (NK) cells are endowed with antiviral properties such as IFN-γ and TNF-α secretion as well as cytotoxicity that could contribute to HBV clearance ( Fisicaro et al, 2019 ). In patients, NK cells are activated during acute HBV infection before the onset of adaptive immunity ( Dunn et al, 2009 ; Fisicaro et al, 2009 ; Zhao et al, 2012 ; Lunemann et al, 2014 ; Yu et al, 2018 ). However, in the chronic phase of the disease, NK cells present impaired functions, which could contribute to viral persistence.…”