Human Hepatitis B Virus Negatively Impacts the Protective Immune Crosstalk Between Natural Killer and Dendritic Cells

Abstract

BaCKgRoUND aND aIMS: Natural killer (NK) cells play a crucial role in the clearance of human viruses but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). Cooperation with dendritic cells (DCs) is pivotal for obtaining optimal NK cell antiviral function; thus, we investigated whether HBV might impact the ability of DCs to sustain NK cell functions. appRoaCH aND ReSUltS: Human DCs were poor stimulators of interferon-gamma (IFNγ) production by NK cells when exposed to HBV, while maintaining the capability to trigger NK cell cytotoxicity. HBV prevented DC maturation but did not affect their expression of human leukocyte antigen class I, thus allowing DCs to evade NK cell lysis. Tolerogenic features of DCs exposed to HBV were further supported by their increased expression of IL-10 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase, which contributed to the impairment of DC-mediated NK cell IFNγ production and proliferation, respectively. HBV could also inhibit the expression of inducible immunoproteasome (iP) subunits on DCs. In fact, NK cells could induce iP subunit expression on DCs, but they failed in the presence of HBV. Remarkably, circulating blood DC antigen1 (BDCA1) + DCs isolated from patients with CHB were functionally compromised, hence altering, in turn, NK cell responses. CoNClUSIoNS:The abnormal NK-DC interplay caused by HBV may significantly impair the efficacy of antiviral immune response in patients with CHB. (Hepatology 2021;74:550-565). HBV is a major cause of inflammatory liver disease of variable severity that affects millions of people worldwide. Despite the availability of vaccine, more than 257 million people are still infected with HBV. (1) The pathophysiology of HBV infection is complex and closely linked to host immune response. An ineffective and weak immune response toward HBV is thought to be the fundamental underlying cause for evolution of HBV infection until the establishment of chronic disease. (2,3) Progression of persistent infection together with cell death and regeneration of infected hepatocytes succeed one another, leading to chronic inflammation and fibrosis often associated with the risk of developing liver cirrhosis and hepatocellular carcinoma. (4)

Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment

“…Although pDCs exist as a small proportion of the total cells in blood, they are the main effector cells producing type I interferon in vivo and play a vital role in HBV infection. However, functional defects in pDCs have been reported in patients with chronic HBV infection ( 18 , 19 , 27 ). At present, the ultimate goal of CHB treatment is to achieve functional cure, which requires antiviral immune response.…”

Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma

“…Excessive activation of immune suppressor cells can lead to persistent HBV infection and progression of HCC. The immunosuppressive effect of cells involved in negative immune regulation causes CD8+ T and NK cells to become exhausted, allowing HBV and HCC tumor cells to escape the immune system [ 22 , 72 , 93 , 94 ]. The key immunosuppressive T cell subset, Treg cells, mainly produces immunosuppressive cytokines including TGF-β, IL-10, and IL-35 [ 72 ].…”

“…A recent study found that plasmacytoid DC function was greatly reduced in patients with CHB, and IL6ST (gp130) played a key role in contributing to DC dysfunction [ 92 ]. Another study showed that HBV causes abnormal NK–DC interplay that may impair the efficacy of antiviral immune responses in patients with CHB [ 93 ].…”

Letter to the Editor: Entecavir Treatment Restores the Anti‐HBV Immune response?

“…With great interest, we read the manuscript by De Pasquale et al ( 1 ) They convincingly showed that dendritic cells (DCs), generated in vitro from monocytes of patients with HBV, have a detrimental effect on the function of natural killer (NK) cells, leading to the insufficient anti‐HBV response observed in patients with chronic HBV. However, many years ago, we conducted a similar study.…”