scholarly journals HBsAg Dampened STING Associated Activation of NK Cells in HBeAg-Negative CHB Patients

2021 ◽  
Vol 22 (14) ◽  
pp. 7643
Author(s):  
Bingqing Zheng ◽  
Yating Yu ◽  
Zhaoyi Pan ◽  
Yujie Feng ◽  
Huajun Zhao ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Chronic Hepatitis ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Cell Recognition ◽  
Dna Sensor ◽  
Healthy Donors ◽  
Chronic Hepatitis B Virus ◽  
B Virus

NK cells play crucial roles in defending against persistent HBV. However, NK cells present dysfunction in chronic hepatitis B virus (CHB) infection, and the associated mechanism is still not fully understood. Except for the regulatory receptors, NK cells could also be regulated by the surface and intracellular pattern recognition receptors (PRRs). In the present study, we found that the level of the adaptor of DNA sensor STING in NK cells was significantly decreased in HBeAg-negative CHB patients, and it was positively associated with the degranulation ability of NK cells. Compared to NK cells from healthy donors, NK cells from HBeAg-negative CHB patients displayed a lower responsiveness to cGAMP stimulation. Further investigation showed that HBsAg could inhibit the STING expression in NK cells and suppress the response of NK cells to cGAMP. Significantly, STAT3 was identified to be a transcription factor that directly regulated STING transcription by binding to the promoter. In addition, STAT3 positively regulated the STING associated IFN-α response of NK cells. These findings suggested that STING is an important adaptor in NK cell recognition and activation, while HBsAg disturbs NK cell function by the STAT3-STING axis, providing a new mechanism of NK disability in HBeAg-negative CHB infection.

scholarly journals Antiviral Treatment Alters the Frequency of Activating and Inhibitory Receptor-Expressing Natural Killer Cells in Chronic Hepatitis B Virus Infected Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Juan Lv ◽  
Qinglong Jin ◽  
Haibo Sun ◽  
Xiumei Chi ◽  
Xiaoli Hu ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Inhibitory Receptor ◽  
Cell Numbers ◽  
Chronic Hepatitis B Virus ◽  
B Virus

Natural killer (NK) cells play a critical role in innate antiviral immunity, but little is known about the impact of antiviral therapy on the frequency of NK cell subsets. To this aim, we performed this longitudinal study to examine the dynamic changes of the frequency of different subsets of NK cells in CHB patients after initiation of tenofovir or adefovir therapy. We found that NK cell numbers and subset distribution differ between CHB patients and normal subjects; furthermore, the association was found between ALT level and CD158b+NK cell in HBV patients. In tenofovir group, the frequency of NK cells increased during the treatment accompanied by downregulated expression of NKG2A and KIR2DL3. In adefovir group, NK cell numbers did not differ during the treatment, but also accompanied by downregulated expression of NKG2A and KIR2DL3. Our results demonstrate that treatment with tenofovir leads to viral load reduction, and correlated with NK cell frequencies in peripheral blood of chronic hepatitis B virus infection. In addition, treatments with both tenofovir and adefovir in chronic HBV infected patients induce a decrease of the frequency of inhibitory receptor+NK cells, which may account for the partial restoration of the function of NK cells in peripheral blood following treatment.

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

2019 ◽  
Vol 70 (3) ◽  
pp. 351-360 ◽  
Author(s):  
Anita Schuch ◽  
Britta Franziska Zecher ◽  
Philipp Andreas Müller ◽  
Margareta P. Correia ◽  
Franziska Daul ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Virus Infection ◽  
Hepatitis B ◽  
Nk Cell ◽  
Hepatitis B Virus Infection ◽  
Effector Functions ◽  
Cell Responses ◽  
Chronic Hepatitis B Virus ◽  
B Virus

scholarly journals Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

2010 ◽  
Vol 6 (12) ◽  
pp. e1001227 ◽  
Author(s):  
Dimitra Peppa ◽  
Lorenzo Micco ◽  
Alia Javaid ◽  
Patrick T. F. Kennedy ◽  
Anna Schurich ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B Virus ◽  
Virus Infection ◽  
Hepatitis B ◽  
Nk Cell ◽  
Hepatitis B Virus Infection ◽  
Chronic Hepatitis B Virus ◽  
B Virus ◽  
Antiviral Function ◽  
Immunosuppressive Cytokines

scholarly journals Adaptive Subsets Limit the Anti-Tumoral NK-Cell Activity in Hepatocellular Carcinoma

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1369
Author(s):  
Charlotte Rennert ◽  
Catrin Tauber ◽  
Pia Fehrenbach ◽  
Kathrin Heim ◽  
Dominik Bettinger ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Cell Subset ◽  
Cell Repertoire ◽  
Healthy Donors ◽  
B Virus ◽  
The Impact

Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the anti-tumoral activity of NK cells in HCC associated with different etiologies, and the impact of the heterogeneous NK cell subset, e.g., adaptive and conventional subsets, are not understood in detail. By comparatively analyzing the NK-cell repertoire in 60 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD), we show in this study that the NK-cell repertoire is linked to HCC etiology, with increased frequencies of adaptive NK cells in Hepatitis B virus (HBV)-associated HCC. Adaptive NK cells exhibited limited anti-tumoral activity toward liver cancer cells; however, this was not a result of a specific NK-cell impairment in HCC but rather represented an intrinsic feature, since the characteristics of circulating and intra-tumoral adaptive NK cells were conserved between HD, HCC and liver cirrhosis patients. Hence, the expansion of adaptive NK cells with reduced anti-tumoral activity, detectable in HBV-associated HCC, may have implications for tumor surveillance and therapy.

scholarly journals Adaptive subsets limit the anti-tumoral NK-cell activity in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Charlotte Rennert ◽  
Catrin Tauber ◽  
Pia Fehrenbach ◽  
Kathrin Heim ◽  
Dominik Bettinger ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Activity ◽  
Cell Subset ◽  
Cell Repertoire ◽  
Healthy Donors ◽  
B Virus ◽  
Infiltrating Lymphocytes

Background and Aims: Hepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the human NK-cell repertoire is highly diverse including conventional and adaptive NK cells that differ in phenotype and effector function. Adaptive NK-cell frequencies are increased in association with HCMV (human cytomegalovirus) seropositivity that is also common in HCC patients. In this study, we aimed to gain a better understanding of the NK-cell repertoire and the associated anti-tumoral activity in HCC patients. Methods: In-depth phenotypic and functional flow-cytometry analyses of the HCMV-associated NK cell-repertoire obtained from 57 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD). Results: First, adaptive subsets are present in all three cohorts with conserved characteristics in patients with liver cirrhosis and HCC. Second, adaptive NK cells can be isolated from HCC tissue however lack features of tissue-residency and thus probably represent circulating/infiltrating lymphocytes. Third, the anti-tumoral activity by adaptive NK cells is reduced compared to conventional NK-cell subsets, also in HCC. Lastly, frequencies of adaptive NK cells were increased in patients suffering from Hepatitis B virus-associated HCC providing a link between etiology and the NK-cell repertoire in HCC. Conclusion: Adaptive NK cells limit the anti-tumoral activitity of NK cells in HCC, especially in association with HBV infection that is accompanied by an expansion of this NK cell subset.

NK Cells in Hodgkin Lymphoma Are Impaired but Can Be Activated

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2182-2182
Author(s):  
Joerg Kessler ◽  
Katrin S. Reiners ◽  
Maike Sauer ◽  
Andreas Engert ◽  
Elke Pogge von Strandmann
Keyword(s):  
Nk Cells ◽  
Hodgkin Lymphoma ◽  
Cell Function ◽  
Nk Cell ◽  
Serum Levels ◽  
Activation Markers ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Healthy Donors ◽  
Cell Inhibition

Abstract Abstract 2182 Introduction: NK cells represent the key component of the innate immune system to recognize and eliminate cancer cells. Defects in NK cell function including impaired cytotoxicity/cytokine secretion, aberrant receptor expression profile, NK cell number and NK cell anergy are reported in non Hodgkin lymphoma and correlate with a bad prognosis. So far, nothing is known about the phenotype of peripheral NK cells and serum levels of ligands for NK cell receptors in Hodgkin Lymphoma (HL) patients. Here, cytotoxicity, expression pattern of activating NK cell receptors and the serum levels of several ligands for the key cytotoxic receptors NKG2D and NKp30 are determined. Methods: The cytotoxicity of NK cells isolated from HL patients was analysed by europium release assay using the HL cell line L428 as target cells. The serum level of the NKp30-ligand BAT3 and ligands for NKG2D (MICA, MICB and ULBP1,2,3) was estimated in sera of 117 HL patients and 40 healthy donors by ELISA. The expression pattern of NKp30, NKp44, NKp46, CD16 and the activation markers CD25, CD69 and CD71 was determined by 4-colour FACS analysis of peripheral blood lymphocytes. Results: The cytotoxicity assays reveal a significantly reduced killing efficacy of NK cells from HL patients against the Hodgkin cell line L428 in comparison to NK cells from healthy donors. Correlating with the impaired NK cell function, we observed that the serum level for BAT3 and MICA was significantly elevated in HL patients, whereas other ligands (MICB and ULBP1,2,3) remained unchanged. NKG2D showed a significantly decreased expression on NK cells of HL patients. No significant difference was observed for all other receptors and activation markers tested. Conclusion: Our results suggest that soluble BAT3 and MICA, ligands for NKp30 and NKG2D, contribute to the NK cell inhibition in HL patients. Since soluble ligands for NK cell receptors are known to inhibit NK cell-cytotoxicity, the release of these ligands might represent an immune escape mechanism of HL tumors to avoid detection and killing by the innate immune system. To overcome NK cell inhibition in HL patients we design, express and purify bispecific proteins (immunoligands) that target NKG2D and a HL-specific tumorantigen. Work to activate HL-derived NK cells with immunoligands ex vivo will be discussed. Disclosures: Engert: Affimed Therapeutics AG: Honoraria, Research Funding.

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