Genetically Associated CD16+56− Natural Killer Cell Interferon (IFN)–αR Expression Regulates Signaling and Is Implicated in IFN-α–Induced Hepatitis C Virus Decline

Conry, Sara J.; Meng, Qian‐Fang; Hardy, Gareth; Yonkers, Nicole L.; Sugalski, Julia M.; Hirsch, Amy; Compan, Anita; Falck‐Ytter, Yngve; Blanton, Ronald E.; Rodrı́guez, Benigno; Anthony, Donald D.

doi:10.1093/infdis/jis027

Cited by 8 publications

(5 citation statements)

References 39 publications

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“…This is in line with the IFN-refractory state of nonresponders, who demonstrate a pre-activated IFN response signature in the liver, and minimal response to exogenous IFN-α treatment [124]. In support of these findings, higher baseline expression of the IFN-α receptor, IFNAR1, is associated with improved response to treatment, in an IFNL3 genotype-dependant manner [125]. Importantly, while nonresponders do not upregulate NKp30 or NKp46 in response to IFN treatment, responders demonstrate an increase in NKp30 or NKp46 following 12 weeks of treatment [96].…”

Section: Effect Of Pegylated Ifn-α/ribavirin-based Therapy On Nk Cellssupporting

confidence: 79%

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

Njiomegnie

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Fewings

et al. 2020

JCM

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Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.

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Section: Effect Of Pegylated Ifn-α/ribavirin-based Therapy On Nk Cellssupporting

confidence: 79%

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

Njiomegnie

Read

Fewings

et al. 2020

JCM

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“…IFN‐αR is involved in anti‐HCV responses as noted by the positive association of its expression on NK cells and a favourable response to Peg‐IFN‐α/RBV . We show that in ART‐treated HIV/HCV co‐infection, a lower IFN‐αR expression may still indicate a lack of innate immune reconstitution by a sustained state of chronic NK activation with lower functionality.…”

Section: Discussionmentioning

confidence: 78%

HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy‐treated HIV/HCV‐co‐infected subjects

Papasavvas

Azzoni

Yin

et al. 2017

Journal of Viral Hepatitis

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The impact of Hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viremic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 HCV genotype 1/HIV co-infected on ART) were studied. Clinical and liver enzymes measurements were performed. Whole blood was analyzed for immune subset changes by flow-cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced Signal Transducer and Activator of Transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production. Statistical analysis was done using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T cell activation/exhaustion, and constitutive STAT-1 phosphorylation compared to HCV. In contrast, CD4+FoxP3+CD25+ frequency, IFN-αR expression on NK cells, as well as constitutive and IFN-α-induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load (vl) and CD4+ T cell count had an opposite effect between the two groups on NK cell activity, and T cell activation respectively. HCV viraemia in antiretroviral -treated HIV/HCV co-infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono-infection. The more pronounced immune modulation noted in antiretroviral treated HIV co-infected / untreated HCV viremic subjects may impact HCV disease progression and/or response to immunotherapy.

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“…A previous work has shown that both glyco- and protein-engineering lead to a higher binding affinity to CD16a. From a mechanistic point of view, these data suggest that this gain in affinity is achieved by different mechanisms ( 35 ), and it has also been shown that CD16a takes effect through several mechansisms ( 36 ). In the present study, we proved that CD16a was expressed in KCs, and we also investigated a profound action mechanism of ADCC in KCs for further.…”

Section: Discussionmentioning

confidence: 89%

Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells

Liu¹,

et al. 2016

International Journal of Molecular Medicine

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FcγRIIIa (CD16) is a low-affinity Fc receptor of IgG. As the idio-binding receptor of IgG Fc, it plays an important role in the antibody-dependent cellular cytotoxicity of natural killer cells. The aim of the present study was to investigate the distribution of Kupffer cells (KCs) and the expression of their surface receptor FcγRIIIa in hepatocellular carcinoma. Furthermore, we also aimed to observe the functional mechanism of FcγRIIIa. Immunohistochemical analysis was employed to study KCs and FcγRIIIa. In order to explore the role of FcγRIIIa in the growth of cancer cells, KCs and H22 tumor cells were co-cultured in different serum. The mRNA expression levels of tumor necrosis factor (TNF)-α and FcγRIIIa were analyzed by RT-qPCR; the TNF-α and FcγRIIIa protein expression levels were examined by enzyme-linked immunosorbent assay and western blot analysis, respectively. Our results showed that the number of Kuppfer cells in cancerous tissues (21.6±7.8) was lower than those in para-cancerous (68.8±9.1) tissues and adjacent normal hepatic tissues (62.0±1.9) (P<0.01); this decreased with the reduction in the differentiation degree of cancer (P<0.05). FcγRIIIa-positive cells were similar in morphology to KCs, and their distributive tendency was coincident (P<0.05). The increase in CD16a mRNA levels in the group treated with immune serum was 3.9-, 4.9- and 3.9-fold greater than that in the ordinary serum group at different time points, and CD16a protein expression also markedly increased (P<0.05). However, these effects were inhibited by the addition of anti-IgG Fc serum (P<0.05). The results of the present study suggested that FcγRIIIa resided in KCs, and it contributed to the inhibition of the growth of liver tumor cells.

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Genetically Associated CD16+56− Natural Killer Cell Interferon (IFN)–αR Expression Regulates Signaling and Is Implicated in IFN-α–Induced Hepatitis C Virus Decline

Abstract: IFN-αR expression on CD16(+)56(-) NK cells during chronic HCV infection may in part be genetically determined, and level of expression regulates IFN-α signaling, which in turn may contribute to control of HCV infection.

Cited by 8 publications

References 39 publications

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection

HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy‐treated HIV/HCV‐co‐infected subjects

Effect of CD16a, the surface receptor of Kupffer cells, on the growth of hepatocellular carcinoma cells

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