HCMV-controlling NKG2C NK cells originate from novel circulating inflammatory precursors.

Background: There is limited knowledge on the origin and development from CD34 precursors of the ample spectrum of human natural killer (NK) cells, particularly of specialized NK subsets.

Objective: This study sought to characterize the NK-cell progeny of CD34DNAM-1CXCR4 and of other precursors circulating in the peripheral blood of patients with chronic viral infections (eg, HIV, hepatitis C virus, cytomegalovirus reactivation).

Methods: Highly purified precursors were obtained by flow cytometric sorting and cultured in standard NK-cell differentiation media (ie, SCF, FLT3, IL-7, IL-15).

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

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).

Accumulation of Circulating CCR7 Natural Killer Cells Marks Melanoma Evolution and Reveals a CCL19-Dependent Metastatic Pathway.

Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients.

PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua.

Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23.

PD-1 in human NK cells: evidence of cytoplasmic mRNA and protein expression.

Under physiological conditions, PD-1/PD-L1 interactions regulate unwanted over-reactions of immune cells and contribute to maintain peripheral tolerance. However, in tumor microenvironment, this interaction may greatly compromise the immune-mediated anti-tumor activity. PD-1 NK cells have been detected in high percentage in peripheral blood and ascitic fluid of ovarian carcinoma patients.

New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression.

Natural killer cells are cytotoxic innate lymphoid cells that play an important role for early host defenses against infectious pathogens and surveillance against tumor. In humans, NK cells may be divided in various subsets on the basis of the relative CD56 expression and of the low-affinity FcγRIIIA CD16. In particular, the two main NK cell subsets are represented by the CD56/CD16 and the CD56/CD16 NK cells.

Updated clinical and biological information from the two-stage phase II study of imatinib mesylate in subjects with relapsed/refractory neuroblastoma.

Several studies support the notion that the kinase inhibitor Imatinib mesylate exerts off-target effects on cells of the immune system. After our first report of continuous daily oral administration in subjects with relapsed/refractory neuroblastoma (NB, EudraCT: 2005-005778-63), here we update the clinical information and report additional information on potential surrogate markers for prediction of efficacy. Peripheral blood (PB) samples collected at study entry and after the first and second cycle of Imatinib mesylate treatment were tested for IFN-, TNF-α, TGF-β, IL-10, CXCL12 and soluble (s) B7-H6 plasma levels.

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor.

The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 regulates NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity.

Analysis of Polymorphism Provides Relevant Information on Centromeric Gene Content.

Four killer cell Ig-like receptor () genes, collectively referred to as framework genes, characterize almost all haplotypes. In particular, and mark the ends of the locus, whereas and are located in the central part. A recombination hot spot, mapped between and , splits the haplotypes into two regions: a centromeric (Cen) region (spanning from to ) and a telomeric region (from to ), both varying in gene content.

Late Development of FcεRγ Adaptive Natural Killer Cells Upon Human Cytomegalovirus Reactivation in Umbilical Cord Blood Transplantation Recipients.

In human natural killer (NK) cells, human cytomegalovirus (HCMV) has been shown to be a driving force capable of inducing the expansion of a highly differentiated NKG2CCD57 subset, persisting over time in both HCMV healthy subjects and umbilical cord blood transplantation (UCBT) recipients experiencing HCMV viral reactivation. In HCMV healthy subjects, such expanded NK-cells are characterized by epigenetic modifications that modulate their phenotypic and functional characteristics. In particular, an enhanced ADCC activity is detectable in NK cells lacking the signaling protein FcεRγ.

Human γδ T-Cells: From Surface Receptors to the Therapy of High-Risk Leukemias.

γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g.

NK Cells Mediate a Crucial Graft-versus-Leukemia Effect in Haploidentical-HSCT to Cure High-Risk Acute Leukemia.

Natural killer (NK) cells are involved in innate defenses against viruses and tumors. Their function is finely tuned by activating and inhibitory receptors. Among the latter, killer immunoglobulin-like receptors and CD94/NKG2A recognize human leukocyte antigen (HLA) Class I molecules, allowing NK cells to discriminate between normal and aberrant cells, as well as to recognize allogeneic cells, because of their ability to sense HLA polymorphisms.

Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56 NKG2A Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

[This corrects the article on p. 798 in vol. 8, PMID: 28769923.

NKG2C memory-like NK cells contribute to the control of HIV viremia during primary infection: Optiprim-ANRS 147.

Natural-killer (NK) cells are important immune effectors during a viral infection. Latent CMV infection is widely spread and was demonstrated to shape the NK cell repertoire through the NKG2C receptor. An expansion of NKG2C NK cells has been reported during primary HIV infection (PHI), but their role is not known.

TGF-β1 Downregulates the Expression of CXCR1 by Inducing miR-27a-5p in Primary Human NK Cells.

Activity of human natural killer (NK) cells against cancer cells is deeply suppressed by TGF-β1, an immunomodulatory cytokine that is released and activated in the tumor microenvironment. Moreover, our previous data showed that TGF-β1 modifies the chemokine receptor repertoire of NK cells. In particular, it decreases the expression of CXCR1 that drives these effectors toward peripheral tissues, including tumor sites.

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56 NKG2A Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Mutations of the recombinase-activating genes 1 and 2 ( and ) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity.

Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages.

Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages.

KIR3DS1-Mediated Recognition of HLA-*B51: Modulation of KIR3DS1 Responsiveness by Self HLA-B Allotypes and Effect on NK Cell Licensing.

Several studies described an association between killer-cell immunoglobulin-like receptor (KIR)/HLA gene combinations and clinical outcomes in various diseases. In particular, an important combined role for KIR3DS1 and HLA-B Bw4-I80 in controlling viral infections and a higher protection against leukemic relapses in donor equipped with activating KIRs in haplo-HSCT has been described. Here, we show that KIR3DS1 mediates positive signals upon recognition of HLA-B*51 (Bw4-I80) surface molecules on target cells and that this activation occurs only in Bw4-I80 individuals, including those carrying particular KIR/HLA combination settings.

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial.

The Innate Immune Cross Talk between NK Cells and Eosinophils Is Regulated by the Interaction of Natural Cytotoxicity Receptors with Eosinophil Surface Ligands.

Previous studies suggested that the cross talk between NK cells and other cell types is crucial for the regulation of both innate and adaptive immune responses. In the present study, we analyzed the phenotypic and functional outcome of the interaction between resting or cytokine-activated NK cells and eosinophils derived from non-atopic donors. Our results provide the first evidence that a natural cytotoxicity receptor (NCR)/NCR ligand-dependent cross talk between NK cells and eosinophils may be important to upregulate the activation state and the effector function of cytokine-primed NK cells.

NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27.

Angiogenesis represents a hallmark of tumor progression in Multiple Myeloma (MM), a still incurable malignancy. Here we analyzed the activity of cytokine-stimulated NK cells against tumor-associated endothelial cells isolated from bone marrow aspirates of MM patients with active disease (MMECs). We show that NK cells activated with optimal doses of IL-15 killed MMECs thanks to the concerted action of multiple activating receptors.

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients.

X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae.

Markers and function of human NK cells in normal and pathological conditions.

Natural killer (NK) cells, the most important effectors of the innate lymphoid cells (ILCs), play a fundamental role in tumor immune-surveillance, defense against viruses and, in general, in innate immune responses. NK cell activation is mediated by several activating receptors and co-receptors able to recognize ligands on virus-infected or tumor cells. To prevent healthy cells from auto-aggression, NK cells are provided with strong inhibitory receptors (KIRs and NKG2A) which recognize HLA class I molecules on target cells and, sensing their level of expression, allow killing of targets underexpressing HLA-class I.

Structural Insights into the Inhibitory Mechanism of an Antibody against B7-H6, a Stress-Induced Cellular Ligand for the Natural Killer Cell Receptor NKp30.

Antibodies have been shown to block signaling through cell surface receptors using several mechanisms. The two most common are binding to the ligand-binding site of the receptor and, conversely, binding to the receptor-binding site of the ligand. Here, we investigated the inhibitory mechanism of an antibody (17B1.