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Stefanie Memmer, Sandra Weil, Steffen Beyer, Tobias Zöller, Eike Peters, Jessica Hartmann, Alexander Steinle, Joachim Koch
The natural cytotoxicity receptor (NCR) NKp30 (CD337) is a key player for NK cell immunosurveillance of infections and cancer. The molecular details of ligand recognition and its connection to CD3ζ signaling remain unsolved. Here, we show that the stalk domain (K129EHPQLGAGTVLLLR143) of NKp30 is very sensitve to sequence alterations, as mutations lead to impaired ligand binding and/or signaling capacity. Surprisingly, the stalk domains of NKp30 and NKp46, another NCR employing CD3ζ for signaling, were not exchangeable without drastic deficiencies in folding, plasma membrane targeting and/or ligand induced receptor signaling...
October 17, 2016: Journal of Biological Chemistry
Alon Vitenshtein, Yoav Charpak-Amikam, Rachel Yamin, Yoav Bauman, Batya Isaacson, Natan Stein, Orit Berhani, Liat Dassa, Moriya Gamliel, Chamutal Gur, Ariella Glasner, Carlos Gomez, Ronen Ben-Ami, Nir Osherov, Brendan P Cormack, Ofer Mandelboim
Natural killer (NK) cells form an important arm of the innate immune system and function to combat a wide range of invading pathogens, ranging from viruses to bacteria. However, the means by which NK cells accomplish recognition of pathogens with a limited repertoire of receptors remain largely unknown. In the current study, we describe the recognition of an emerging fungal pathogen, Candida glabrata, by the human NK cytotoxic receptor NKp46 and its mouse ortholog, NCR1. Using NCR1 knockout mice, we observed that this receptor-mediated recognition was crucial for controlling C...
October 12, 2016: Cell Host & Microbe
Vincent Sam Yong Tchang, Michael Stiess, Kerstin Siegmund, Urs Karrer, Jean Pieters
Coronin 1, a member of the evolutionary conserved WD repeat protein family of coronin proteins is expressed in all leukocytes, but a role for coronin 1 in natural killer (NK) cell homeostasis and function remains unclear. Here, we have analyzed the number and functionality of NK cells in the presence and absence of coronin 1. In coronin 1-deficient mice, absolute NK cell numbers and phenotype were comparable to wild type mice in blood, spleen and liver. Following in vitro stimulation of the activating NK cell receptors NK1...
September 20, 2016: Immunobiology
Mariella Della Chiesa, Silvia Pesce, Letizia Muccio, Simona Carlomagno, Simona Sivori, Alessandro Moretta, Emanuela Marcenaro
Human NK cells are distinguished into CD56(bright)CD16(-) cells and CD56(dim)CD16(+) cells. These two subsets are conventionally associated with differential functional outcomes and are heterogeneous with respect to the expression of KIR and CD94/NKG2 heterodimers that represent the two major types of HLA-class I-specific receptors. Recent studies indicated that immature CD56(bright) NK cells, homogeneously expressing the inhibitory CD94/NKG2A receptor, are precursors of CD56(dim) NK cells that, in turn, during their process of differentiation, lose expression of CD94/NKG2A and subsequentially acquire inhibitory KIRs and LIR-1...
2016: Frontiers in Immunology
Asma Beldi-Ferchiou, Marion Lambert, Stéphanie Dogniaux, Frédéric Vély, Eric Vivier, Daniel Olive, Stéphanie Dupuy, Frank Levasseur, David Zucman, Céleste Lebbé, Damien Sène, Claire Hivroz, Sophie Caillat-Zucman
Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors...
September 20, 2016: Oncotarget
Nayeli Goreti Nieto-Velázquez, Yessica Dorin Torres-Ramos, José Luis Muñoz-Sánchez, Lorena Espinosa-Godoy, Susana Gómez-Cortés, José Moreno, Mario Adán Moreno-Eutimio
Human natural killer (NK) cells are considered professional cytotoxic cells that are integrated into the effector branch of innate immunity during antiviral and antitumoral responses. The purpose of this study was to examine the peripheral distribution and expression of NK cell activation receptors from the fresh peripheral blood mononuclear cells of 30 breast cancer patients prior to any form of treatment (including surgery, chemotherapy, and radiotherapy), 10 benign breast pathology patients, and 24 control individuals...
October 2016: Translational Oncology
Anja Sipka, Brianna Pomeroy, Suzanne Klaessig, Ynte Schukken
Natural killer (NK) cells are early responders in bacterial infections but their role in bovine mastitis has not been characterized. For the first time, we show the presence of NK cells (NKp46(+)/CD3(-)) in bovine mammary gland tissue after an intramammary challenge with Escherichia (E.) coli. A small number of NK cells was detected in milk from quarters before and during an E. coli challenge. In vitro cultures of primary bovine mammary gland epithelial cells stimulated with UV irradiated E. coli induced significant migration of peripheral blood NK cells (pbNK) within 2h...
October 2016: Comparative Immunology, Microbiology and Infectious Diseases
Wolfgang Merkt, Maren Claus, Norbert Blank, Michael Hundemer, Adelheid Cerwenka, Hanns-Martin Lorenz, Carsten Watzl
BACKGROUND: The role of natural killer (NK) cells in granulomatosis with polyangiitis (GPA) is poorly understood. We recently reported that peripheral blood NK cell percentages correlate with the suppression of GPA activity (cohort I). The purpose of the current study was to further characterize NK cell subsets, phenotype and function in a second GPA cohort (cohort II). METHODS: Peripheral blood lymphocyte subsets were analyzed at a clinical diagnostic laboratory...
2016: Arthritis Research & Therapy
Alexandre Valayer, Deborah Brea, Laurie Lajoie, Leslie Avezard, Lucie Combes-Soia, Valerie Labas, Brice Korkmaz, Gilles Thibault, Thomas Baranek, Mustapha Si-Tahar
Polymorphonuclear neutrophils (PMNs) can contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Mechanisms by which this immunoregulation process occurs remain incompletely understood. Here, we focused on the effect of human neutrophil-derived serine proteases on NKp46, a crucial activating receptor expressed on NK cells. We used flow cytometry, Western blotting, and mass spectrometry (MS) analysis to reveal that cathepsin G [CG; and not elastase or proteinase 3 (PR3)] induces a time- and concentration-dependent, down-regulatory effect on NKp46 expression through a restricted proteolytic mechanism...
September 1, 2016: Journal of Leukocyte Biology
Nandini B Makwana, Bree Foley, Silvia Lee, Sonia Fernandez, Ashley B Irish, Patricia Price
Whilst it is established that CMV disease affects NK-cell profiles, the functional consequences of asymptomatic CMV replication are unclear. Here we characterise NK cells in clinically stable renal transplant recipients (RTRs; n = 48) >2 years after transplantation. RTRs and age-matched controls (n = 32) were stratified by their CMV serostatus and the presence of measurable CMV DNA. CMV antibody or CMV DNA influenced expression of NKG2C, LIR-1, NKp30, NKp46 and FcRγ, a signalling adaptor molecule, on CD56(dim) NK cells...
August 26, 2016: European Journal of Immunology
Xiaoyan Li, Min Zhang, Jing Liu, Zhanlian Huang, Qiyi Zhao, Yuehua Huang, Xu Li, Zhiliang Gao
BACKGROUND: Although numerous epidemiological studies indicate that hepatitis B virus-related liver fibrosis (HBV-LF), particularly cirrhosis, represents the main risk factor for liver cancer development, the mechanisms determining the persistence of fibrosis and liver cancer pathogenesis are still poorly defined. Few studies have investigated the status of NK cells during different stages of HBV-LF. METHODS: Liver tissues at least 3 cm away from the tumour site and peripheral blood were obtained simultaneously from 32 HBV-infected patients undergoing surgery for HCC at the medical centre of Sun Yat-sen University...
October 2016: European Journal of Clinical Investigation
Chang Gun Cho, Sung Ho Gong, Hee-Bok Kim, Jae-Jun Song, Joo Hyun Park, Yun-Sung Lim, Seok-Won Park
The objective of this study was to evaluate the role of group 3 innate lymphoid cells (ILC3) in the middle ear (ME) mucosal response to bacterial infection in a rat model. To confirm the role of ILC3 in bacterially induced otitis media (OM), the serum concentrations of IL-17 and IL-22 were determined by ELISA, and the tissue expression of IL-17 and IL-22 in infected ME mucosa was assessed by immunohistochemical staining. Immunohistochemical staining of specific cell surface markers was also assessed to confirm the origin of the cells expressing IL-17 and IL-22...
September 2016: International Journal of Pediatric Otorhinolaryngology
Upkar S Gill, Dimitra Peppa, Lorenzo Micco, Harsimran D Singh, Ivana Carey, Graham R Foster, Mala K Maini, Patrick T F Kennedy
NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are 'primed' with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs...
August 2016: PLoS Pathogens
Cathal Harmon, Mark W Robinson, Ronan Fahey, Sarah Whelan, Diarmaid D Houlihan, Justin Geoghegan, Cliona O'Farrelly
The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations...
September 2016: European Journal of Immunology
Joanna S Kritikou, Carin I M Dahlberg, Marisa A P Baptista, Arnika K Wagner, Pinaki P Banerjee, Lavesh Amar Gwalani, Cecilia Poli, Sudeepta K Panda, Klas Kärre, Susan M Kaech, Fredrik Wermeling, John Andersson, Jordan S Orange, Hanna Brauner, Lisa S Westerberg
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts...
2016: Scientific Reports
Kerstin H Mair, Maria Stadler, Stephanie C Talker, Hilde Forberg, Anne K Storset, Andrea Müllebner, J Catharina Duvigneau, Sabine E Hammer, Armin Saalmüller, Wilhelm Gerner
The CD3(-)NKp46(+) phenotype is frequently used for the identification of natural killer (NK) cells in various mammalian species. Recently, NKp46 expression was analyzed in more detail in swine. It could be shown that besides CD3(-)NKp46(+) lymphocytes, a small but distinct population of CD3(+)NKp46(+) cells exists. In this study, we report low frequencies of CD3(+)NKp46(+) lymphocytes in blood, lymph nodes, and spleen, but increased frequencies in non-lymphatic organs, like liver and lung. Phenotypic analyses showed that the majority of CD3(+)NKp46(+) cells coexpressed the CD8αβ heterodimer, while a minor subset expressed the TCR-γδ, which was associated with a CD8αα(+) phenotype...
2016: Frontiers in Immunology
Yong Zou, Zhi-Xing Song, Ying Lu, Xiao-Li Liang, Qing Yuan, Si-Hong Liao, Jun-Jie Bao
Accumulating evidence has shown that allogeneic blood transfusions can induce significant immunosuppression in recipients, and thereby increase the risk of postoperative infection and/or tumor relapse. Although it is well known that natural killer (NK) cells are responsible for the immunodepression effects of transfusion, the underlying mechanisms remain obscure. In this study, we investigated the role of NK cells in transfusion-induced immunodepression in β-thalassemia major. The proportion of circulating NK cells and the expression of NK receptors (NKG2A, CD158a, NKP30, NKP46 and NKG2D) as well as CD107a were detected by multicolor flow cytometry...
August 2016: Journal of Huazhong University of Science and Technology. Medical Sciences
Roberto García-López, María Eugenia de la Morena-Barrio, Laia Alsina, Belén Pérez-Dueñas, Jaak Jaeken, Mercedes Serrano, Mercedes Casado, Trinidad Hernández-Caselles
BACKGROUND: PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder. OBJECTIVE: To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors...
2016: PloS One
Victor Cortez, Marco Colonna
Innate lymphoid cells (ILCs) are a heterogeneous population of cells with diverse roles in immune responses. Three major groups of ILCs have been defined on the basis of similarity in their production of signature cytokines, developmental requirements, and phenotypic markers. Group 1 ILCs produce IFN-γ, express the T-box transcription factors (TF) Eomesodermin (Eomes) and/or T-bet. Group 2 ILCs secrete IL-5 and IL-13, express the TF GATA-3, and are identified by the expression of KLRG1, the receptor IL-7 (IL7R, also known as CD127), and the receptor for IL-33 (IL33R)...
July 6, 2016: Immunology Letters
Orlando Nascimento Terra Junior, Gabriel de Carvalho Maldonado, Guilherme Rohem Alfradique, Vinicius da Cunha Lisboa, Adriano Arnóbio, Dirce Bonfim de Lima, Hilda Rachel Diamond, Maria Helena Faria Ornellas de Souza
The NCR receptors play a fundamental role in the cytotoxicity mediated by NK cells against tumor cells. In the current study, we investigated possible HIV/AIDS-related changes in the expression of the NCR receptors comparing healthy donors, HIV/AIDS patients, and HIV/AIDS patients with cancer (HIV/AIDSWC). The NCRs were quantified in NK cells (NK(dim) and NK(bright)) and T lymphocytes from peripheral blood samples by flow cytometry. We found a significant decrease in the frequency of NK cells expressing NKp46 in HIV/AIDS group (p = 0...
2016: TheScientificWorldJournal
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