scholarly journals Effect of interleukins (IL-2, IL-15, IL-18) on receptors activation and cytotoxic activity of natural killer cells in breast cancer cell

2020 ◽  
Vol 20 (2) ◽  
pp. 822-832 ◽  
Author(s):  
Wahyu Widowati ◽  
Diana K Jasaputra ◽  
Sutiman B Sumitro ◽  
Mochammad A Widodo ◽  
Tjandrawati Mozef ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Receptor ◽  
Mcf7 Cells ◽  
Activating Receptors ◽  
Tnf Α ◽  
Ifn Γ

Introduction: Breast cancer is one of the leading cause of cancer deaths in women. Metastasis in BC is caused by immuno- surveillance deficiency, such NK cell maturation, low NK activity and decreasing cytotoxicity. This study was performed to improve activating receptors and cytotoxicity of NK cells using interleukins (ILs). Methods: Human recombinant IL-2, -15, and -18 were used to induce NK cells. We measured the activating and inhibiting receptors, proliferation activity of NK cells, and the cytotoxicity of NK cells on BC cells (MCF7). The effects of ILs were tested on the NK cell receptors CD314, CD158a and CD107a with flowcytometry, proliferation at various incubation times with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and concen- trations of TNF-α and IFN-γ by NK cells with ELISA. Results: ILs increased NK cell receptor levels (CD314, CD158a, and CD107a) at 24 hours of incubation. ILs increased NK cell viability, which increased with longer incubation. Moreover, ILs-induced NK cells inhibited proliferation in MCF7 cells, as well as increased TNF-α, IFN-γ, PRF1 and GzmB secretion. Conclusion: IL-2, IL-15, and IL-18 improved activating receptors and proliferation of NK cells. IL-induced NK cells in- creased TNF-α, IFN-γ, PRF1 and GzmB secretion and cytotoxic activity on BC cells. High NK cell numbers increased BC cell growth inhibition. Keywords: Activator; breast cancer; interleukins; natural killer; receptor.

scholarly journals Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

2017 ◽  
Vol 9 (5) ◽  
pp. 511-525 ◽  
Author(s):  
Sophie M. Poznanski ◽  
Amanda J. Lee ◽  
Tina Nham ◽  
Evan Lusty ◽  
Margaret J. Larché ◽  
...  
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

scholarly journals TIGIT Expression Positively Associates with NK Cell Function in AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5250-5250 ◽  
Author(s):  
Bei Jia ◽  
Chenchen Zhao ◽  
David F. Claxton ◽  
W. Christopher Ehmann ◽  
Witold B. Rybka ◽  
...  
Keyword(s):  
Nk Cells ◽  
Therapeutic Strategy ◽  
Cell Function ◽  
Nk Cell ◽  
Granzyme B ◽  
Healthy Controls ◽  
Functional Studies ◽  
Activating Receptors ◽  
Tnf Α ◽  
Ifn Γ

Abstract Natural killer (NK) cells are essential innate immune effectors with promising anti-leukemia activity in acute myeloid leukemia (AML). However, clinical success of applying NK cells in AML treatment has not been achieved. A better understanding of the regulatory mechanisms for NK cell function is important to optimize this therapeutic strategy. T cell immunoglobulin and ITIM domain (TIGIT) is a recently identified inhibitory receptor expressed on T cells and NK cells. Multiple studies including ours have demonstrated its suppressive effect in anti-tumor CD8 T cell response. However whether and how TIGIT impacts NK cells in AML is unknown. Here we performed phenotypic and functional studies on NK cells derived from patients with newly diagnosed AML (n=30). Cells collected from healthy individuals (n=18) were used as controls. TIGIT expression and their contributions to NK cell function in AML were assessed. Peripheral blood samples were first examined by flow cytometry for the frequency of NK cells (defined as CD56+CD3-). The percentage of NK cells among peripheral blood mononuclear cells (PBMCs) in AML patients is comparable with that of healthy controls. In contrast, when we performed functional analysis to assess NK cells for cytokine release upon in vitro stimulation with a human leukemia cell line K562, we observed significantly lower intracellular production of IFN-γ in cells from AML patients compared with that of healthy controls. Consistently NK cells from AML patients expressed less Perforin, indicating a compromised killing capacity. We next evaluated the expression of TIGIT on CD56+CD3- NK cells. As some AML blasts and monocytes also express CD56, we performed multichannel flow cytometry and carefully gated out other cell components when assessing TIGIT expression. To our surprise, we observed a significantly lower frequency of TIGIT-expressing NK cells in AML compared with that of healthy controls (36.82 ±4.543% vs. 48.9±3.818%, P=0.0463). This data indicated that low-TIGIT expression associates with impaired NK cell function and AML progression. We further examined the phenotype and functional status of TIGIT+ NK cells. Expression of activating receptors (CD16 and CD160) and inhibiting receptors (KIR and NKG2A) on TIGIT+ vs. TIGIT- NK cells were analyzed. We observed a significant higher expression of CD16 (51.27±9.009% vs. 20.63±5.334%, P=0.0001) and CD160 (39.84±6.447% vs. 21.24±4.287%, P=0.0103) on TIGIT+ NK cells compared with that of TIGIT- NK cells. By contrast, TIGIT+ NK cells expressed lower KIR (24.06±3.796% vs. 43.59±6.96%, P=0.0046) and NKG2A (7.658±1.717% vs. 18.68±4.256%, P=0.0167) than TIGIT- NK cells. Importantly, functional studies demonstrated an elevated expression of Granzyme B and increased cytokine (IFN-γ and TNF-α) production by TIGIT+ NK cells compared with TIGIT- NK cells (IFN-γ, P=0.0283; TNF-α P=0.0347; Granzyme B, P=0.0493). These data suggest that TIGIT expression on NK cells associated with activated and high functional status. Collectively, our study demonstrates that 1) in line with lower capacity to produce IFN-γ, NK cells from AML patients express less frequency of TIGIT compared with healthy individuals; 2) TIGIT+ NK cells from AML patients express high levels of activating receptors and are highly functional manifested by more cytokine production and enhanced expression of Granzyme B compared with TIGIT- NK cells. These results indicate that in AML patient, TIGIT may contribute to the upregulation of NK cell function. This is in contrast to the observations of CD8 T cells in which TIGIT plays a suppressive role. Targeting TIGIT for cancer treatment is currently under active development. Our findings bring a call for caution on the TIGIT-targeted therapeutic strategy in AML as TIGIT might be a double-edged sword in anti-leukemia immune regulation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Echinococcus multilocularis induces surface high expression of inhibitory killer immunoglobulin‐like receptor on natural killer cells

2021 ◽  
Vol 49 (5) ◽  
pp. 78-86
Author(s):  
Bayindala ◽  
He Huang ◽  
Song Gao ◽  
Xinjian Xu
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Echinococcus Multilocularis ◽  
Nk Cell ◽  
Single Cells ◽  
Granzyme B ◽  
Inhibitory Receptor ◽  
Tnf Α ◽  
Ifn Γ

Alveolar echinococcosis (AE) is a malignant and fatal parasitic disease caused by the larvae of Echinococcus multilocularis (E. multilocularis), which inhibits the activity and proliferation of natural killer (NK) cells. In this study, the functional alteration of hepatic NK cells and their related molecules were studied. The AE-infected patient’s tissue was fixed with formalin, embedded in paraffin, and stained with Masson’s trichrome or hematoxylin and eosin (H&E). Single cells from AE-infected patient or E. multilocularis-infected mice were blocked with Fc-receptor (FcR), and stained with monoclonal antibodies, including CD16, CD56, CD3, KIR2DL1, granzyme B, perforin, Interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF- α) or isotype control, to measure molecules and cytokines of NK cells and analyzed by flow cytometry. The Sirius red staining was used to quantitate hepatic fibrosis by calculating quantitative collagen deposition. AE can adjust both the number of hepatic CD56+ NK cells andits KIR2DL1 expression processes. Moreover, the overexpression of KIR2DL1 in NK cells could downregulate the functioning of immune cells in the liver area close to parasitic lesions. The number and dysfunction of NK cells in E. multilocularis infection could be related to the molecule dynamics of cell surface inhibitory receptor Ly49A, leading to hepatic damage and progression of fibrosis. This study illustrated significant increase in hepatic fibrogenesisand apparent upregulation of hepatic CD56+ NK cell population and its KIR2DL1 expression in AE-infected patients. This opposite variation might be related to the impaired NK cells functioning, such as granzyme B, IFN-γ, and TNF-α secretion. In addition, the cell surface inhibitory receptor Ly49A was related to the intracellular cytokine secretion functions of NK cells.

scholarly journals Human Leukocyte Antigen-G Inhibits the Anti-Tumor Effect of Natural Killer Cells via Immunoglobulin-Like Transcript 2 in Gastric Cancer

2017 ◽  
Vol 44 (5) ◽  
pp. 1828-1841 ◽  
Author(s):  
Rui Wan ◽  
Zi-Wei Wang ◽  
Hui Li ◽  
Xu-Dong Peng ◽  
Guang-Yi Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Tnf Α ◽  
Ifn Γ ◽  
Human Leukocyte Antigen G

Background/Aims: Human leukocyte antigen-G (HLA-G) plays an important role in inhibiting natural killer (NK) cell function and promoting immune escape. However, the specific mechanism of HLA-G on NK in gastric cancer (GC) remains not well understood. This study investigated the expression of HLA-G in GC and the role of HLA-G-effected NK cells in GC progression. Methods: HLA-G expression in GC tissues obtained from 49 patients with GC was analyzed by immunohistochemistry and western blot. The number of tumor-infiltrating NK cells and the expression of their surface receptors were analyzed by immunohistochemistry and flow cytometry, respectively. The effect of HLA-G on NK cell proliferation was examined by Cell Counting Kit-8 (CCK8) assay. LDH release assay was used to evaluate the effect of HLA-G on the cytotoxic activity of NK cells, and the levels of IFN-γ and TNF-α in the co-cultured supernatant were detected by ELISA. Mice bearing a xenograft tumor model were used to examine the effect of HLA-G on the anti-tumor effect of NK cells. Results: HLA-G positive expression was detected in most of the GC tissues, and was correlated with the adverse prognosis of the disease. The expression of HLA-G was negatively associated with the number of tumor-infiltrating NK cells. Furthermore, GC cell lines with overexpressed HLA-G revealed their ability to inhibit the cell proliferation and cytotoxic activity of NK-92MI cells, and reduce the secretion of IFN-γ and TNF-α through immunoglobulin-like transcript 2 (ILT2). Finally, this in vivo experiment was able to prove that HLA-G can inhibit the anti-tumor effect of NK cells through ILT2. Conclusion: The expression of HLA-G was strongly correlated with the adverse prognosis of GC. The reason may be that it inhibits the proliferation and cytotoxic activity of infiltrating NK cells through ILT2.

scholarly journals Nfil3-independent lineage maintenance and antiviral response of natural killer cells

2013 ◽  
Vol 210 (13) ◽  
pp. 2981-2990 ◽  
Author(s):  
Matthew A. Firth ◽  
Sharline Madera ◽  
Aimee M. Beaulieu ◽  
Georg Gasteiger ◽  
Eliseo F. Castillo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Lineage ◽  
Term Survival ◽  
Recombinant Viruses ◽  
Activating Receptors ◽  
Ifn Γ ◽  
Deficient Mice

Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3−/− mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3−/− NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15–dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.

scholarly journals Cytokine-Induced Apoptosis of Human Natural Killer Cells Identifies a Novel Mechanism to Regulate the Innate Immune Response

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 910-918 ◽  
Author(s):  
Mary E. Ross ◽  
Michael A. Caligiuri
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Innate Immune Response ◽  
Cell Apoptosis ◽  
Nk Cell ◽  
Innate Immune ◽  
Tnf Α ◽  
Ifn Γ ◽  
Induced Apoptosis

Abstract Interferon-γ (IFN-γ) is critical for an effective innate immune response against infection. A combination of interleukins (ILs) derived from activated T cells (IL-2) and monocytes (IL-12), or monocytes alone (IL-15 and IL-12), induces optimal production of IFN-γ from natural killer (NK) cells. The mechanism by which human NK cells downregulate their production of IFN-γ is unknown. Here we show that the same cytokines that induce human NK cell IFN-γ production subsequently induce apoptosis of the NK cells. Fas, bcl-2, or bax do not appear to be involved in this process. The mechanism of cytokine-induced apoptosis of human NK cells appears to involve NK cell production of tumor necrosis factor-α (TNF-α). Neutralization of TNF-α or inhibition of TNF-α binding to the p80 TNF-α receptor partially inhibited apoptosis. Transforming growth factor-β, which inhibits cytokine-induced NK cell production of IFN-γ and TNF-α, also decreased cytokine-induced NK cell apoptosis. Costimulation of a CD3−CD56+ NK leukemia cell line with IL-2 and IL-12 or IL-15 and IL-12 induced apoptosis in vitro, which increased when combined with a chemotherapeutic agent. In summary, costimulation of human NK cells via the IL-2 receptor and the IL-12 receptor induces significant IFN-γ production, followed by NK cell apoptosis and a decline in IFN-γ production. Hence, cytokines that activate this innate immune response may also serve to limit it via apoptosis. This novel observation may have implications for the regulation of the innate immune response during infection, the toxicity of combination cytokine therapy, and the treatment of NK cell leukemia.

scholarly journals Interaction between HLA-G and NK cell receptor KIR2DL4 orchestrates HER2-positive breast cancer resistance to trastuzumab

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Guoxu Zheng ◽  
Zhangyan Guo ◽  
Weimiao Li ◽  
Wenjin Xi ◽  
Baile Zuo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Receptor ◽  
Her2 Positive ◽  
Trastuzumab Treatment ◽  
Ifn Γ ◽  
Nk Cell Receptor ◽  
Positive Breast Cancer

AbstractDespite the successful use of the humanized monoclonal antibody trastuzumab (Herceptin) in the clinical treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, the frequently occurring drug resistance remains to be overcome. The regulatory mechanisms of trastuzumab-elicited immune response in the tumor microenvironment remain largely uncharacterized. Here, we found that the nonclassical histocompatibility antigen HLA-G desensitizes breast cancer cells to trastuzumab by binding to the natural killer (NK) cell receptor KIR2DL4. Unless engaged by HLA-G, KIR2DL4 promotes antibody-dependent cell-mediated cytotoxicity and forms a regulatory circuit with the interferon-γ (IFN-γ) production pathway, in which IFN-γ upregulates KIR2DL4 via JAK2/STAT1 signaling, and then KIR2DL4 synergizes with the Fcγ receptor to increase IFN-γ secretion by NK cells. Trastuzumab treatment of neoplastic and NK cells leads to aberrant cytokine production characterized by excessive tumor growth factor-β (TGF-β) and IFN-γ, which subsequently reinforce HLA-G/KIR2DL4 signaling. In addition, TGF-β and IFN-γ impair the cytotoxicity of NK cells by upregulating PD-L1 on tumor cells and PD-1 on NK cells. Blockade of HLA-G/KIR2DL4 signaling improved the vulnerability of HER2-positive breast cancer to trastuzumab treatment in vivo. These findings provide novel insights into the mechanisms underlying trastuzumab resistance and demonstrate the applicability of combined HLA-G and PD-L1/PD-1 targeting in the treatment of trastuzumab-resistant breast cancer.

scholarly journals Natural Killer Cells: Potential Biomarkers and Therapeutic Target in Autoimmune Diseases?

2021 ◽  
Vol 12 ◽  
Author(s):  
Elena Gianchecchi ◽  
Domenico V. Delfino ◽  
Alessandra Fierabracci
Keyword(s):  
Systemic Sclerosis ◽  
Autoimmune Diseases ◽  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell

Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.

Flt3 Ligand Promotes the Generation of a Distinct CD34+Human Natural Killer Cell Progenitor That Responds to Interleukin-15

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3647-3657 ◽  
Author(s):  
Haixin Yu ◽  
Todd A. Fehniger ◽  
Pascal Fuchshuber ◽  
Karl S. Thiel ◽  
Eric Vivier ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Stromal Cells ◽  
Nk Cell ◽  
Cell Development ◽  
Lower Percentage ◽  
Human Natural Killer Cell ◽  
Flt3 Ligand ◽  
Interleukin 15

Abstract Interleukin-15 (IL-15) is produced by human bone marrow (BM) stromal cells and can induce CD34+ hematopoietic progenitor cells (HPCs) to differentiate into CD56+CD3−natural killer (NK) cells in the absence of stromal cells. IL-15 mediates its effects by signaling through the β and γcchains of the IL-2/15 receptor (R). The c-kit ligand (KL), also produced by stromal cells, enhances the expansion of NK cells from CD34+ HPCs in the presence of IL-15, but alone has no ability to differentiate NK cells. Mice deficient in KL do not appear to have a quantitative deficiency in NK cells, suggesting that other stromal cell factors may contribute to NK cell expansion. Flt3 ligand (FL) is also produced by BM stromal cells and has homology with KL. Furthermore, mice with a targeted disruption of the FL gene have reduced numbers of NK cells. We evaluated here the effects of FL on human NK cell development and expansion from CD34+ HPCs. Like KL, FL significantly enhanced the expansion of NK cells from CD34+ HPCs in the presence of IL-15, compared with IL-15 alone. However, FL alone had no effect on NK cell differentiation. We therefore explored the mechanism by which FL promotes IL-15–mediated NK cell development. FL was found to induce IL-2/15Rβ (CD122) expression on CD34bright HPCs. The CD34brightCD122+ cell coexpressed CD38, but lacked expression of CD7, CD56, NK cell receptors (NKRs), or cytotoxic activity in the absence of IL-15. Using limiting dilution analysis in the presence of IL-15 alone, we demonstrated that the FL-induced CD34brightCD122+ HPCs had an NK cell precursor frequency 20- to 60-fold higher than the CD34dim/negCD122− HPCs and 65- to 235-fold higher than fresh CD34+ HPCs. KL had similar effects as FL, but induced a significantly lower percentage of CD34brightCD122+ cells (P ≤ .01). Both FL and KL also increased IL-15R transcript in CD34+ HPCs. Culture of CD34+ HPCs in FL or KL, followed by culture in IL-15 alone, induced expression of both C-type lectin and Ig-superfamily NKRs on CD56+ cells. These data collectively support a role for FL in early human NK cell development. FL or KL generate a unique CD34brightCD122+CD38+ human NK cell intermediate from CD34+ HPCs that lacks NK features yet is IL-15–responsive. IL-15 is then required for the induction of CD56 and NKRs, LGL morphology, cytotoxic activity, and the ability to produce abundant cytokines and chemokines.

scholarly journals Aberrant anti-viral response of natural killer cells in severe asthma

2020 ◽  
Vol 55 (5) ◽  
pp. 1802422
Author(s):  
Justine Devulder ◽  
Cécile Chenivesse ◽  
Valérie Ledroit ◽  
Stéphanie Fry ◽  
Pierre-Emmanuel Lobert ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Severe Asthma ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Asthma Patients ◽  
Ifn Γ

Rhinovirus infections are the main cause of asthma exacerbations. As natural killer (NK) cells are important actors of the antiviral innate response, we aimed at evaluating the functions of NK cells from severe asthma patients in response to rhinovirus-like molecules or rhinoviruses.Peripheral blood mononuclear cells from patients with severe asthma and healthy donors were stimulated with pathogen-like molecules or with the rhinoviruses (RV)-A9 and RV-2. NK cell activation, degranulation and interferon (IFN)-γ expression were analysed.NK cells from severe asthma patients were less cytotoxic than those from healthy donors in response to toll-like receptor (TLR)3, TLR7/8 or RV-A9 but not in response to RV-2 stimulation. Furthermore, when cultured with interleukin (IL)-12+IL-15, cytokines which are produced during viral infections, NK cells from patients with severe asthma were less cytotoxic and expressed less IFN-γ than NK cells from healthy donors. NK cells from severe asthmatics exhibited an exhausted phenotype, with an increased expression of the checkpoint molecule Tim-3.Together, our findings indicate that the activation of NK cells from patients with severe asthma may be insufficient during some but not all respiratory infections. The exhausted phenotype may participate in NK cell impairment and aggravation of viral-induced asthma exacerbation in these patients.

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