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

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.

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

Cells ◽

10.3390/cells10061369 ◽

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.

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The Role of Natural Killer Cells in Autoimmune Diseases

Frontiers in Immunology ◽

10.3389/fimmu.2021.622306 ◽

2021 ◽

Vol 12 ◽

Cited By ~ 1

Author(s):

Umut Can Kucuksezer ◽

Esin Aktas Cetin ◽

Fehim Esen ◽

Ilhan Tahrali ◽

Nilgun Akdeniz ◽

...

Keyword(s):

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Lupus Erythematosus ◽

Cell Biology ◽

Nk Cell ◽

Cell Activity ◽

Cell Subset ◽

Therapeutic Interventions ◽

Surface Receptors

Natural killer (NK) cells, the large granular lymphocytes differentiated from the common lymphoid progenitors, were discovered in early 1970’s. They are members of innate immunity and were initially defined by their strong cytotoxicity against virus-infected cells and by their important effector functions in anti-tumoral immune responses. Nowadays, NK cells are classified among the recently discovered innate lymphoid cell subsets and have capacity to influence both innate and adaptive immune responses. Therefore, they can be considered as innate immune cells that stands between the innate and adaptive arms of immunity. NK cells don’t express T or B cell receptors and are recognized by absence of CD3. There are two major subgroups of NK cells according to their differential expression of CD16 and CD56. While CD16+CD56dim subset is best-known by their cytotoxic functions, CD16-CD56bright NK cell subset produces a bunch of cytokines comparable to CD4+ T helper cell subsets. Another subset of NK cells with production of interleukin (IL)-10 was named as NK regulatory cells, which has suppressive properties and could take part in immune-regulatory responses. Activation of NK cells is determined by a delicate balance of cell-surface receptors that have either activating or inhibitory properties. On the other hand, a variety of cytokines including IL-2, IL-12, IL-15, and IL-18 influence NK cell activity. NK-derived cytokines and their cytotoxic functions through induction of apoptosis take part in regulation of the immune responses and could contribute to the pathogenesis of many immune mediated diseases including ankylosing spondylitis, Behçet’s disease, multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and type-1 diabetes. Dysregulation of NK cells in autoimmune disorders may occur through multiple mechanisms. Thanks to the rapid developments in biotechnology, progressive research in immunology enables better characterization of cells and their delicate roles in the complex network of immunity. As NK cells stand in between innate and adaptive arms of immunity and “bridge” them, their contribution in inflammation and immune regulation deserves intense investigations. Better understanding of NK-cell biology and their contribution in both exacerbation and regulation of inflammatory disorders is a requisite for possible utilization of these multi-faceted cells in novel therapeutic interventions.

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Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

Cancers ◽

10.3390/cancers12082187 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2187

Author(s):

Raffaella Meazza ◽

Michela Falco ◽

Fabrizio Loiacono ◽

Paolo Canevali ◽

Mariella Della Chiesa ◽

...

Keyword(s):

Acute Leukemia ◽

Nk Cells ◽

Nk Cell ◽

Functional Characterization ◽

Cell Subset ◽

Cell Phenotype ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Γδt Cells ◽

Effector Cells

NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.

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Cytomegalovirus Reactivation Shapes NK Cells Diversity Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.4588.4588 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4588-4588

Author(s):

Li Li ◽

Muharrem Muftuoglu ◽

Han Chen ◽

Duncan Mak ◽

Elif Gokdemir ◽

...

Keyword(s):

Nk Cells ◽

Viral Infections ◽

Nk Cell ◽

Cmv Infection ◽

Cell Recovery ◽

Cell Repertoire ◽

Hematopoietic Stem ◽

Healthy Donors ◽

Before And After ◽

Cell Diversity

Abstract Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are key players in immune defense against viral infections and malignant transformation. NK cell numbers generally recover within the first month post-transplant, but the acquisition of mature NK cell phenotype and full functional competency can take over 6 months and is influenced by various host and donor factors. Cytomegalovirus (CMV) infection has been shown to modulate NK cell maturation after HSCT. The diversity of the NK cell repertoire is dictated by a variety of combinatorially expressed activating and inhibitory receptors that dictate the NK activation status. Moreover, whereas the expression of inhibitory receptors is primarily genetically determined, environmental factors such as viral infections influence the expression of activating receptors to a great extent.. We propose that assessment of diversity could provide a different perspective for the evaluation of the NK cell compartment after HSCT, since it is a quantitative measure that takes into account both the number and evenness of the different NK subpopulations. To better understand the factors that influence NK cell recovery after cord blood (CB) transplant (CBT) and specifically the influence of cytomegalovirus (CMV) infection on NK cell maturity, we used 40-parameter mass cytometry (CyTOF) to interrogate the NK cell repertoire. A panel including 37 monoclonal antibodies was designed to recognize NK cells lineage markers and receptors as well as intracellular markers such as transcription factors and adaptor proteins. We first evaluated and compared the diversity of NK cells in 10 CB units and peripheral blood (PB) from 20 healthy donors. We then examined the diversity of NK cells before and after CBT in 22 serially collected blood samples from in 10 CBT recipients. NK cell diversity was significantly lower in CB (mean 574, range 417-891) compared to PB samples from healthy donors (mean 3792, range 1284-5079; P=0.001), indicating less diversification within the naive CB NK compartment. After CBT, NK cell diversity was lower at earlier time point (Day30) (mean 1129, range 428-1768) compared to PB from healthy donors; P=0.01. The diversity of NK cells increased gradually over time following CBT (Day 30 mean 1129 range 428-1768; Day 60, mean 1185, range 515-1864; 4 months, mean 1711 range 597-2640). We also compared the diversity of NK cells in the PB of healthy CMV seronegative (n=10) and seropositive adult donors (n=10). The diversity of NK cells was higher in CMV seropositive vs. CMV seronegative healthy donors (3887 vs 2473; P=0.04). This difference in NK diversity was even more pronounced within the KIR positive (mean 1701, range, 981-2152) compared to the KIR negative subset (mean 551, range 456-647; P=0.02), indicating that CMV infection increases the richness of mature NK cells. In keeping with these findings, CMV infection after CBT was associated with a significantly greater diversity of NK cells, especially within the KIR positive compartment (mean 604, range 207-1035) compared to the KIR negative subset (mean 283, 257-457; P=0.025). However, in CMV negative patients, we found no difference in diversity within the KIR positive and negative subsets (mean 1120 vs. 1366; P=0.28). Taken together, these data suggest that NK cell diversity reflects NK cells differentiation and maturation, and that CMV shapes NK cell diversity, especially within the KIR positive compartment. To further understand how CMV influences NK cells diversity, we examined the top 15 NK cell subsets and their distribution at multiple timepoints before and after CMV reactivation post-CBT. CMV infection post-CBT was associated with a significant change in the distribution of NK subsets within the KIR positive population, with the top 15 subsets prior to CMV reactivation being mostly replaced by the emergence of new subsets. In contrast, the top 15 subsets within the KIR negative NK population remained stable. These data suggest that CMV drives NK cell maturation by differentiating KIR positive NK cells. In summary, we used high-dimensional single-cell data to evaluate NK cell reconstitution following HSCT. These data can help us better understand the biology of NK cell recovery after HSCT and discover the functional significance of NK cell diversity in the setting of viral infections. Disclosures Champlin: Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

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Myeloma cells induce the accumulation of activated CD94low NK cells by cell-to-cell contacts involving CD56 molecules

Blood Advances ◽

10.1182/bloodadvances.2019000953 ◽

2020 ◽

Vol 4 (10) ◽

pp. 2297-2307 ◽

Cited By ~ 2

Author(s):

Chiara Barberi ◽

Claudia De Pasquale ◽

Alessandro Allegra ◽

Giacomo Sidoti Migliore ◽

Daniela Oliveri ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Cell Subset ◽

Newly Diagnosed ◽

Effector Cells ◽

Cell Contacts ◽

Combination Treatments ◽

Healthy Donors ◽

Innate Effector

Abstract Natural killer (NK) cells represent innate effector cells potentially able to play a role during the immune response against multiple myeloma (MM). To better define the distribution and the specific properties of NK cell subsets during MM disease, we analyzed their features in the bone marrow and peripheral blood of newly diagnosed MM patients. Our findings revealed that, in both compartments, NK cells were more abundant than in healthy donors. Among total MM-NK cells, a significant increase of CD94lowCD56dim NK cell subset was observed, which already appears in clinical precursor conditions leading to MM, namely monoclonal gammopathy of undetermined significance and smoldering MM, and eventually accumulates with disease progression. Moreover, a consistent fraction of CD94lowCD56dim NK cells was in a proliferation phase. When analyzed for their killing abilities, they represented the main cytotoxic NK cell subset against autologous MM cells. In vitro, MM cells could rapidly induce the expansion of the CD94lowCD56dim NK cell subset, thus reminiscent of that observed in MM patients. Mechanistically, this accumulation relied on cell to cell contacts between MM and NK cells and required both activation via DNAM-1 and homophilic interaction with CD56 expressed on MM cells. Considering the growing variety of combination treatments aimed at enhancing NK cell-mediated cytotoxicity against MM, these results may also be informative for optimizing current immunotherapeutic approaches.

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Intratumor Regulatory Noncytotoxic NK Cells in Patients with Hepatocellular Carcinoma

Cells ◽

10.3390/cells10030614 ◽

2021 ◽

Vol 10 (3) ◽

pp. 614

Author(s):

Alessandra Zecca ◽

Valeria Barili ◽

Danila Rizzo ◽

Andrea Olivani ◽

Elisabetta Biasini ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nk Cells ◽

Nk Cell ◽

Functional Characterization ◽

Cell Subset ◽

Cytotoxic Potential ◽

Tnf Α ◽

Oncogenic Function

Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56BRIGHTCD16− NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6+) NK cells were reduced in the tumors where T-bethiEomeslo expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a+Eomes+ NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6−, T-bethiEomeslo, and CD49a+Eomes+ NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function.

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NK cells acquire CCR5 and CXCR4 by trogocytosis in people living with HIV-1

10.1101/2021.12.21.473773 ◽

2021 ◽

Author(s):

Martin Villalba ◽

Dang-Nghiem Vo ◽

Nicolas Leventoux ◽

Mauricio Campos-Mora ◽

Sandrine Gimenez ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Cell Activity ◽

People Living With Hiv ◽

Hiv Patients ◽

Antiviral Immune Response ◽

Healthy Donors ◽

T Cell Lines ◽

Hiv 1

NK cells play a major role in the antiviral immune response, including against HIV-1. HIV patients have impaired NK cell activity with decrease in CD56dim NK cells and increase in CD56-CD16+ subset and recently it has been proposed that a population of CD56+NKG2C+KIR+CD57+ cells represents antiviral memory NK cells. Antiretroviral therapy (ART) partly restores the functional activity of this lymphocyte lineage. NK cells when interacting with their targets can gain antigens from them by the process of trogocytosis. Here we show that NK cells can obtain CCR5 and CXCR4, but barely CD4, from T cell lines by trogocytosis in vitro. By UMAP (Uniform Manifold Approximation and Projection), we show that aviremic HIV patients have unique NK cell clusters that encompass for cells expressing CCR5, NKG2C and KIRs, but lack CD57 expression. Viremic patients have a larger proportion of CXCR4+ and CCR5+ NK cells than healthy donors (HD) and this is largely increased in CD107+ cells, suggesting a link between degranulation and trogocytosis. In agreement, UMAP identified a specific NK cell cluster in viremic HIV patients, which contains most of the CD107a+, CCR5+ and CXCR4+ cells. However, this cluster lacks NKG2C expression. Therefore, NK cells can gain CCR5 and CXCR4 by trogocytosis, which depends on degranulation.

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Anti-Leukemia Effects of NK Cell-Derived Exosomes

Blood ◽

10.1182/blood-2019-125430 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3223-3223

Author(s):

Michael Boyiadzis ◽

Chang Sook Hong ◽

Theresa L Whiteside

Keyword(s):

Nk Cells ◽

Cell Lines ◽

Nk Cell ◽

Granzyme B ◽

Cell Activity ◽

Leukemia Cells ◽

Target Cells ◽

Nk Cell Activity ◽

Transmission Electron ◽

Healthy Donors

Introduction: Exosomes are 30-150 nm-sized extracellular vesicles originating from the endocytic compartment of parent cells. The exosome molecular cargo reflects the content of its cells of origin and is delivered to recipient cells in a protective glycol-lipid bilayer without degradation. Because of their small size, exosomes freely circulate within the body, can reach the bone marrow, and can cross biological barriers. Natural killer (NK) cells play a critical role in the innate immune response through their capacity to lyse malignant cells without prior antigen-specific priming. Importantly, NK cell activity is reduced in patients with acute myeloid leukemia (AML) relative to that in healthy donors. To overcome the decreased NK cell activity in AML, several therapeutic strategies have been evaluated for safety and efficacy, both in transplant and non-transplant settings, using autologous and allogeneic activated NK cells. Since NK cell-derived exosomes acquire tumor-killing abilities from the parent NK cells, we hypothesize that NK cell-derived exosomes by transferring exosome content to leukemia blasts can induce the death of these target cells. In the current study, we evaluated the in vitro anti-leukemia effects of NK cell-derived exosomes. Methods: Exosomes were isolated from the supernatants of NK cells obtained from healthy donors (n=12) using mini-size exclusion chromatography (mini-SEC). Protein levels, number and size (qNano), and exosome morphology using transmission electron microscopy were determined. The exosome cargo was studied by Western blots and on-bead flow cytometry for NK cell activating and inhibitory receptors, immune inhibitory molecules, and for perforin and granzyme B. Cytotoxicity of the NK cell-derived exosomes for AML cell lines (Kasumi, MLL-1) and primary leukemia blasts was measured using flow cytometry-based assays. Results: Activated human NK cells produced large quantities of exosomes. Transmission electron microscopy showed the presence of vesicles that were uniform in size (30-150nm in diameter) by NanoSight measurement. Confocal imaging of labeled NK cell-derived exosomes interacting with leukemia cells showed that they are rapidly internalized by leukemic targets. NK cell-derived exosomes carried activating NK cell receptor NKG2D, natural cytotoxicity receptors, perforin, granzyme B, transforming growth factor beta (TGF-β), killer-cell immunoglobulin-like receptors, and PD-1. NK cell-derived exosomes were co-incubated with target cells, AML cell lines and primary leukemia cells, at different exosome:target (E:T) ratios using escalating doses of exosomes (10-70 µg). NK cell-derived exosomes mediated strong anti-leukemic activity against AML cell lines and primary leukemic blasts. Importantly, with higher doses of exosomes, higher levels of cytotoxicity were observed, suggesting that exosome-mediated lysis is concentration dependent. NK cell-derived exosomes mediated leukemia killing via different cell death pathways including apoptosis and necroptosis. Conclusion: NK cell-derived exosomes mediating cytotoxicity against leukemic targets represents a novel therapeutic modality for patients with AML. Disclosures No relevant conflicts of interest to declare.

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Changes in NK Cell Subsets and Receptor Expressions in HIV-1 Infected Chronic Patients and HIV Controllers

Frontiers in Immunology ◽

10.3389/fimmu.2021.792775 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhi Zhang ◽

Ying Zhou ◽

Jing Lu ◽

Yuan-Fang Chen ◽

Hai-Yang Hu ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Cell Subset ◽

Chronic Patients ◽

Activating Receptors ◽

Healthy Donors ◽

Tnf Α ◽

Plasma Cytokines ◽

Hiv Controllers ◽

Hiv 1

Natural killer (NK) cells are major effectors of the innate immune response and purported to play an influential role in the spontaneous control of HIV infection. In the present study, we compared the phenotypes of NK cells in the peripheral blood of three groups of subjects with chronic HIV-1 infection, HIV controllers, and healthy donors. The results showed that CD56+/CD16- NK cell subsets decreased in chronic patients and remained unchanged in controllers. Notably, we found that people living with chronic HIV-1 infection had suppressed NKp80, NKp46, and NKG2D expressions on NK cells compared to healthy donors, while HIV controllers remained unchanged. In contrast, NKG2D expression was substantially higher in controllers than in chronic patients (M=97.67, p<0.001). There were no significant differences in inhibitory receptors KIR3DL1 and KIR2DL1 expressions. In addition, plasma cytokine IFN-γ, TNF-α and IL-12showed higher levels in HIV controllers compared to chronic patients. Overall, our study revealed that, as compared to chronic patients, HIV controllers show an increased activating receptors expression and higher number ofCD56+/CD16-NK cell subset, with increased expression levels of plasma cytokines, suggesting that higher immune activation in controllers may have a key role in killing and suppressing HIV.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22147643 ◽

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.

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