Surface Receptors that Regulate the NK Cell Function: Beyond the NK Cell Scope

Abstract Tryptophan (Trp) catabolism mediated by indoleamine 2,3-dioxygenase (IDO) plays a central role in the regulation of T-cell–mediated immune responses. In this study, we also demonstrate that natural killer (NK)–cell function can be influenced by IDO. Indeed, l-kynurenine, a Trp-derived catabolite resulting from IDO activity, was found to prevent the cytokine-mediated up-regulation of the expression and function of specific triggering receptors responsible for the induction of NK-cell–mediated killing. The effect of l-kynurenine appears to be restricted to NKp46 and NKG2D, while it does not affect other surface receptors such as NKp30 or CD16. As a consequence, l-kynurenine–treated NK cells display impaired ability to kill target cells recognized via NKp46 and NKG2D. Instead, they maintain the ability to kill targets, such as dendritic cells (DCs), that are mainly recognized via the NKp30 receptor. The effect of l-kynurenine, which is effective at both the transcriptional and the protein level, can be reverted, since NK cells were found to recover their functional competence after washing.

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Sialic Acids and Their Influence on Human NK Cell Function

Cells ◽

10.3390/cells10020263 ◽

2021 ◽

Vol 10 (2) ◽

pp. 263

Author(s):

Philip Rosenstock ◽

Thomas Kaufmann

Keyword(s):

Nk Cells ◽

Immune Cells ◽

Cell Function ◽

Nk Cell ◽

Sialic Acids ◽

Innate Immune ◽

Target Cells ◽

Carbon Backbone ◽

Nk Cell Receptors ◽

Cell Inhibition

Sialic acids are sugars with a nine-carbon backbone, present on the surface of all cells in humans, including immune cells and their target cells, with various functions. Natural Killer (NK) cells are cells of the innate immune system, capable of killing virus-infected and tumor cells. Sialic acids can influence the interaction of NK cells with potential targets in several ways. Different NK cell receptors can bind sialic acids, leading to NK cell inhibition or activation. Moreover, NK cells have sialic acids on their surface, which can regulate receptor abundance and activity. This review is focused on how sialic acids on NK cells and their target cells are involved in NK cell function.

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Coexistence of inhibitory and activating killer-cell immunoglobulin-like receptors to the same cognate HLA-C2 and Bw4 ligands confer breast cancer risk

Scientific Reports ◽

10.1038/s41598-021-86964-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Elham Ashouri ◽

Karan Rajalingam ◽

Shaghik Barani ◽

Shirin Farjadian ◽

Abbas Ghaderi ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Cancer ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Human Leukocyte ◽

Hla Class I ◽

Risk Scores ◽

Hla Ligands ◽

Nk Cytotoxicity

AbstractHuman leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. Breast cancer (BC) patients exhibit reduced NK-cytotoxicity in peripheral blood. To test the hypothesis that certain KIR-HLA combinations impairing NK-cytotoxicity predispose to BC risk, we analyzed KIR and HLA polymorphisms in 162 women with BC and 278 controls. KIR-Bx genotypes increased significantly in BC than controls (83.3% vs. 71.9%, OR 1.95), and the increase was more pronounced in advanced-cancer (OR 5.3). No difference was observed with inhibitory KIR (iKIR) and HLA-ligand combinations. The activating KIR (aKIR) and HLA-ligand combinations, 2DS1 + C2 (OR 2.98) and 3DS1 + Bw4 (OR 2.6), were significantly increased in advanced-BC. All patients with advanced-cancer carrying 2DS1 + C2 or 3DS1 + Bw4 also have their iKIR counterparts 2DL1 and 3DL1, respectively. Contrarily, the 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls. These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. These data provide a new framework for improving the utility of genetic risk scores for individualized surveillance.

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The effect of IL-2 stimulation and treatment of TRPM3 on channel co-localisation with PIP2 and NK cell function in myalgic encephalomyelitis/chronic fatigue syndrome patients

Journal of Translational Medicine ◽

10.1186/s12967-021-02974-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Natalie Eaton-Fitch ◽

Hélène Cabanas ◽

Stanley du Preez ◽

Donald Staines ◽

Sonya Marshall-Gradisnik

Keyword(s):

Chronic Fatigue Syndrome ◽

Nk Cells ◽

Cell Function ◽

Nk Cell ◽

Chronic Fatigue ◽

Signalling Pathways ◽

Cell Cytotoxicity ◽

Fatigue Syndrome ◽

Intracellular Signalling Pathways ◽

Nk Cell Cytotoxicity

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious multifactorial disorder. The origin remains ambiguous, however reduced natural killer (NK) cell cytotoxicity is a consistent immunological feature of ME/CFS. Impaired transient receptor potential melastatin 3 (TRPM3), a phosphatidylinositol dependent channel, and impaired calcium mobilisation have been implicated in ME/CFS pathology. This investigation aimed to examine the localisation of TRPM3 at the NK cell plasma membrane and co-localisation with phosphatidylinositol 4,5-bisphosphate (PIP2). The effect of IL-2 priming and treatment using pregnenolone sulfate (PregS) and ononetin on TRPM3 co-localisation and NK cell cytotoxicity in ME/CFS patients and healthy controls (HC) was also investigated. Methods NK cells were isolated from 15 ME/CFS patients and 15 age- and sex-matched HC. Immunofluorescent technique was used to determine co-localisation of TRPM3 with the NK cell membrane and with PIP2 of ME/CFS patients and HC. Flow cytometry was used to determine NK cell cytotoxicity. Following IL-2 stimulation and treatment with PregS and ononetin changes in co-localisation and NK cell cytotoxicity were measured. Results Overnight treatment of NK cells with PregS and ononetin resulted in reduced co-localisation of TRPM3 with PIP2 and actin in HC. Co-localisation of TRPM3 with PIP2 in NK cells was significantly reduced in ME/CFS patients compared with HC following priming with IL-2. A significant increase in co-localisation of TRPM3 with PIP2 was reported following overnight treatment with ononetin within ME/CFS patients and between groups. Baseline NK cell cytotoxicity was significantly reduced in ME/CFS patients; however, no changes were observed following overnight incubation with IL-2, PregS and ononetin between HC and ME/CFS patients. IL-2 stimulation significantly enhanced NK cell cytotoxicity in HC and ME/CFS patients. Conclusion Significant changes in co-localisation suggest PIP2-dependent TRPM3 function may be impaired in ME/CFS patients. Stimulation of NK cells with IL-2 significantly enhanced cytotoxic function in ME/CFS patients demonstrating normal function compared with HC. A crosstalk exists between IL-2 and TRPM3 intracellular signalling pathways which are dependent on Ca2+ influx and PIP2. While IL-2R responds to IL-2 binding in vitro, Ca2+ dysregulation and impaired intracellular signalling pathways impede NK cell function in ME/CFS patients.

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Biologia futura: embryo–maternal communication via progesterone-induced blocking factor (PIBF) positive embryo-derived extracellular vesicles. Their role in maternal immunomodulation

Biologia Futura ◽

10.1007/s42977-020-00060-2 ◽

2021 ◽

Author(s):

Julia Szekeres-Bartho ◽

Timea Csabai ◽

Eva Gorgey

Keyword(s):

Extracellular Vesicles ◽

Cell Function ◽

Nk Cell ◽

Immune Functions ◽

Transplantation Immunity ◽

Blocking Factor ◽

Cytokine Balance ◽

Favourable Environment ◽

Normal Gestation

AbstractPaternal antigens expressed by the foetus are recognized as foreign. Therefore,—according to the rules of transplantation immunity—the foetus ought to be “rejected”. However, during normal gestation, maternal immune functions are re-adjusted, in order to create a favourable environment for the developing foetus. Some of the mechanisms that contribute to the altered immunological environment, for example, the cytokine balance and NK cell function, with special emphasis on the role of progesterone and the progesterone-induced blocking factor (PIBF) will be reviewed.

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Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

Cancers ◽

10.3390/cancers13071577 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1577

Author(s):

Matteo Tanzi ◽

Michela Consonni ◽

Michela Falco ◽

Federica Ferulli ◽

Enrica Montini ◽

...

Keyword(s):

Acute Leukemia ◽

Nk Cells ◽

Tumor Cells ◽

Cell Function ◽

Nk Cell ◽

Autologous Tumor ◽

Lymphoid Leukemia ◽

Hematopoietic Stem ◽

Solid Malignancies

The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.

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Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

Journal of Experimental Medicine ◽

10.1084/jem.20062447 ◽

2007 ◽

Vol 204 (4) ◽

pp. 853-863 ◽

Cited By ~ 115

Author(s):

Karine Crozat ◽

Kasper Hoebe ◽

Sophie Ugolini ◽

Nancy A. Hong ◽

Edith Janssen ◽

...

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Cell Function ◽

Nk Cell ◽

Lymphocytic Choriomeningitis ◽

Chromosome 11 ◽

Familial Hemophagocytic Lymphohistiocytosis ◽

Cytokine Levels ◽

Antigen Presenting ◽

Type 3 ◽

Mouse Chromosome 11

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.

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Distinct Requirements for IFNs and STAT1 in NK Cell Function

The Journal of Immunology ◽

10.4049/jimmunol.165.7.3571 ◽

2000 ◽

Vol 165 (7) ◽

pp. 3571-3577 ◽

Cited By ~ 143

Author(s):

Chien-Kuo Lee ◽

Dharma T. Rao ◽

Rachel Gertner ◽

Ramon Gimeno ◽

Alan B. Frey ◽

...

Keyword(s):

Cell Function ◽

Nk Cell

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The effect of genetic variants affecting NK cell function on cardiovascular health and the burden of CMV

Human Immunology ◽

10.1016/j.humimm.2017.10.003 ◽

2017 ◽

Vol 78 (11-12) ◽

pp. 747-751 ◽

Cited By ~ 3

Author(s):

Shelley Waters ◽

Silvia Lee ◽

Jacquita S. Affandi ◽

Ashley Irish ◽

Patricia Price

Keyword(s):

Genetic Variants ◽

Cardiovascular Health ◽

Cell Function ◽

Nk Cell

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Abstract WP319: miRNA Screening of Natural Killer Cell Identifies miR-1224 as a Post-Transcriptional Regulator of NK Cell Function After Ischemic Stroke

Stroke ◽

10.1161/str.51.suppl_1.wp319 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yan Feng ◽

Hui Zhao ◽

Fu-Dong Shi ◽

Weina Jin

Keyword(s):

Ischemic Stroke ◽

Cerebral Ischemia ◽

Nk Cells ◽

Expression Profile ◽

Mirna Expression ◽

Cell Function ◽

Nk Cell ◽

Killer Cell ◽

Mirna Expression Profile ◽

Control Group

Objectives: To screen miRNA profile of peripheral NK cells in ischemic stroke mouse model and investigate a most promising candidate (miR-1224) for post-transcriptional regulation of NK cell function after ischemic stroke. Methods: Mice were subjected to a 60 min focal cerebral ischemia produced by transient intraluminal occlusion of MCAO. For NK cell isolation, cell suspensions from the spleens after reperfusion were enriched for NK cells using magnetic-bead sorting system after staining with anti-NK1.1 microbeads. The nCounter Mouse miRNA array was used to analyze miRNA expression profile in splenic NK cells over the time course of experimental ischemic stroke. Based on the miRNA data, we further in vitro modulated miR-1224 in NK cells using mimics or inhibitor, then injected i.v into Rag2-/-γc-/- recipient mice. Neurological function score was compared and spontaneous infection was assessed by pulmonary bacteria colony culture, and changes in potential signaling pathway (SP1/TNF-α) were verified by rt-PCR and western blot. Results: Through miRNA expression profile analysis, we have identified significant changes at each time point in peripheral NK cells after cerebral ischemia. Among all screened miRNA, miR-1224 remarkably increased in MCAO group, which was verified by PCR. Then isolated NK cells treated with mimics or inhibitors, were transferred to Rag2-/-γc-/- recipient mice. Compared with WT mice, Rag2-/-γc-/- mice with miR-1224 inhibitor exhibited increased NK cell number, enhanced NK cell activation/cytotoxicity feature, as well as better neurological behaviors and reduced pulmonary infection after MCAO. Moreover, compared with the control group, NK cells with miR-1224 inhibitor showed significantly increased SP1 gene and protein phosphorylation. As SP1 gene is one of the potential targets of miR-1224, this study suggests that miR-1224 may regulate NK cell function after MCAO, which is associated with SP1 pathway. Conclusion: The miRNA profiling of splenic NK cells provided insight into the functional mechanism and signaling pathways underlying the distinct organ-specific NK cell properties, which will contribute to the better understanding of NK cell mediated immune-response in relation to different stages of stroke.

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