23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article
      1 , 2 , 3 , 2 , 4 , 3 , 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 10 , 12 , 13 , 13 , 10 , 13 , 14 , 6 , 7 , 6 , 7 , 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 21 , 22 , 18 , 23 , 13 , 24 , 25 , 26 , 27 , 23 , 28 , 29 , 18 , 30 , 31 , 32 , 33 , 34 , 35 , 29 , 36 , 37 , 37 , 2 , * , 1 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      natural killer cells, recombinase-activating genes, non-homologous end joining, immunodeficiency, CD56, interferon-γ, degranulation

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mutations of the recombinase-activating genes 1 and 2 ( RAG1 and RAG2) 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 Rag −/− natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56 bright CD16 −/int CD57 cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: found
          • Article: not found

          HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C.

          The protein HLA-E is a non-classical major histocompatibility complex (MHC) molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Here we report the identification of ligands for HLA-E. We constructed tetramers in which recombinant HLA-E and beta2-microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to phycoerythrin-labelled Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKGK2B and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIR). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK-cell clones. A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK-cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Activation, coactivation, and costimulation of resting human natural killer cells.

            Natural killer (NK) cells possess potent perforin- and interferon-gamma-dependent effector functions that are tightly regulated. Inhibitory receptors for major histocompatibility complex class I display variegated expression among NK cells, which confers specificity to individual NK cells. Specificity is also provided by engagement of an array of NK cell activation receptors. Target cells may express ligands for a multitude of activation receptors, many of which signal through different pathways. How inhibitory receptors intersect different signaling cascades is not fully understood. This review focuses on advances in understanding how activation receptors cooperate to induce cytotoxicity in resting NK cells. The role of activating receptors in determining specificity and providing redundancy of target cell recognition is discussed. Using Drosophila insect cells as targets, we have examined the contribution of individual receptors. Interestingly, the strength of activation is not determined simply by additive effects of parallel activation pathways. Combinations of signals from different receptors can have different outcomes: synergy, no enhancement over individual signals, or additive effects. Cytotoxicity requires combined signals for granule polarization and degranulation. The integrin leukocyte function-associated antigen-1 contributes a signal for polarization but not for degranulation. Conversely, CD16 alone or in synergistic combinations, such as NKG2D and 2B4, signals for phospholipase-C-gamma- and phosphatidylinositol-3-kinase-dependent degranulation.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.

              We have previously shown that NKG2C(+) NK cells from CMV naive umbilical cord blood grafts expand preferentially in recipients after CMV reactivation, representing a primary NK cell response after hematopoietic cell transplantation. In this study, recipients of adult donor hematopoietic cell transplantation were assessed to evaluate the role of donor/recipient CMV serostatus on the expression and function of NKG2C(+) NK cells to determine responses to secondary CMV events. Expansion of NKG2C(+) NK cells was seen following clinical CMV reactivation. However, they also expanded in the absence of detectable CMV viremia when both the donor and recipient were CMV seropositive. Upregulation of NKG2C was observed in NK cells from CMV-positive recipients receiving grafts from CMV-seropositive or -seronegative donors. These in vivo-expanded NKG2C(+) NK cells had an increased capacity for target cell-induced cytokine production, expressed an inhibitory killer Ig-like receptor for self-HLA and preferentially acquired CD57. Most importantly, NKG2C(+) NK cells transplanted from seropositive donors exhibit heightened function in response to a secondary CMV event compared with NKG2C(+) NK cells from seronegative donors. We conclude that NKG2C(+) memory-like NK cells are transplantable and require active or latent (subclinical) expression of CMV Ag in the recipient for clonal expansion of NK cells previously exposed to CMV in the donor.
                Bookmark

                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/441358
                URI : http://frontiersin.org/people/u/110359
                URI : http://frontiersin.org/people/u/317372
                URI : http://frontiersin.org/people/u/435789
                URI : http://frontiersin.org/people/u/28385
                URI : http://frontiersin.org/people/u/39391
                URI : http://frontiersin.org/people/u/23773
                URI : http://frontiersin.org/people/u/257764
                URI : http://frontiersin.org/people/u/246499
                URI : http://frontiersin.org/people/u/423946
                URI : http://frontiersin.org/people/u/206934
                URI : http://frontiersin.org/people/u/446740
                URI : http://frontiersin.org/people/u/69818
                URI : http://frontiersin.org/people/u/388621
                URI : http://frontiersin.org/people/u/157839
                URI : http://frontiersin.org/people/u/294102
                URI : http://frontiersin.org/people/u/375840
                URI : http://frontiersin.org/people/u/26023
                URI : http://frontiersin.org/people/u/246621
                URI : http://frontiersin.org/people/u/25319
                URI : http://frontiersin.org/people/u/435886
                URI : http://frontiersin.org/people/u/378345
                URI : http://frontiersin.org/people/u/104283
                URI : http://frontiersin.org/people/u/136734
                URI : http://frontiersin.org/people/u/100065
                URI : http://frontiersin.org/people/u/23588
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                17 July 2017
                2017
                : 8
                : 798
                Affiliations
                [1] 1Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, United States
                [2] 2Department of Molecular and Translational Medicine, University of Brescia , Brescia, Italy
                [3] 3“A. Nocivelli Institute for Molecular Medicine”, Pediatric Clinic, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia , Brescia, Italy
                [4] 4Hospital de Niños Ricardo Gutiérrez , Buenos Aires, Argentina
                [5] 5Department of Pediatrics, Faculty of Medicine, Kuwait University , Kuwait City, Kuwait
                [6] 6DPUO, Division of Immuno-Infectivology, University Department of Pediatrics, Bambino Gesù Children’s Hospital , Rome, Italy
                [7] 7School of Medicine, University of Tor Vergata , Rome, Italy
                [8] 8Pediatric Allergy Immunology and Blood and Marrow Transplant Division, University of California San Francisco, Benioff Children’s Hospital , San Francisco, CA, United States
                [9] 9Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center , Cincinnati, OH, United States
                [10] 10Institute for Immunity and Transplantation, University College London , London, United Kingdom
                [11] 11Division of Pediatric Hematology, Children’s Hospital Orange County, University of California Irvine , Orange County, CA, United States
                [12] 12Department of Immunology, Royal Free London NHS Foundation Trust , London, United Kingdom
                [13] 13Division of Immunology, Boston Children’s Hospital , Boston, MA, United States
                [14] 14Division of Allergy and Immunology, Southwestern Medical Center, University of Texas , Dallas, TX, United States
                [15] 15Division of Hematology/Oncology/BMT, Children’s Mercy Hospital & Clinics , Kansas City, MO, United States
                [16] 16Department of Pediatrics, Brown University , Providence, RI, United States
                [17] 17Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD, United States
                [18] 18Department of Paediatrics, National University Hospital , Singapore, Singapore
                [19] 19Department of Immunology-Histocompatibility, “Aghia Sophia” Children’s Hospital , Athens, Greece
                [20] 20Division of Pediatric Immunology, Hospital Luis Calvo Mackenna , Santiago, Chile
                [21] 21Department of Pediatrics, Division of Allergy and Immunology, Hofstra Northwell School of Medicine, Hofstra University , Great Neck, NY, United States
                [22] 22Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center (AMC), University of Amsterdam , Amsterdam, Netherlands
                [23] 23Department of Experimental and Clinical Sciences, University of Brescia , Brescia, Italy
                [24] 24Department of Pediatrics, University Hospitals Leuven , Leuven, Belgium
                [25] 25Transplantation Branch, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Rockville, MD, United States
                [26] 26Pediatric Hematology-Immunology Department, Hospital Necker-Enfants Malades, Institut Imagine, AP-HP, Paris Descartes University, Sorbonne-Paris-Cité , Paris, France
                [27] 27Division of Hematology-Oncology, Boston Children’s Hospital , Boston, MA, United States
                [28] 28Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY, United States
                [29] 29Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University , Konya, Turkey
                [30] 30Pediatric Immunology Unit, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv, Israel
                [31] 31Department of Pediatrics and Immunology, Seattle Children’s Hospital, University of Washingtin , Seattle, WA, United States
                [32] 32Division of Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, South Korea
                [33] 33Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital , St. Petersburg, FL, United States
                [34] 34Department of Paediatric Immunology, Great North Children’s Hospital , Newcastle Upon Tyne, United Kingdom
                [35] 35Institute of Cellular Medicine, Newcastle University , Newcastle Upon Tyne, United Kingdom
                [36] 36Department of Laboratory Medicine, Boston Children’s Hospital , Boston, MA, United States
                [37] 37Molecular Immunology Laboratories, Department of Experimental Medicine, University of Genoa , Genoa, Italy
                Author notes

                Edited by: Megan Anne Cooper, Washington University in St. Louis, United States

                Reviewed by: Yenan Bryceson, Karolinska Institutet, Sweden; Emily Mace, Baylor College of Medicine, United States

                *Correspondence: Silvia Parolini, silvia.parolini@ 123456unibs.it ; Luigi D. Notarangelo, luigi.notarangelo2@ 123456nih.gov

                These authors have contributed equally to this work.

                Specialty section: This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.00798
                5511964
                28769923
                23042a91-d090-472b-bc36-c6a5a2c335c0
                Copyright © 2017 Dobbs, Tabellini, Calzoni, Patrizi, Martinez, Giliani, Moratto, Al-Herz, Cancrini, Cowan, Bleesing, Booth, Buchbinder, Burns, Chatila, Chou, Daza-Cajigal, Ott de Bruin, de la Morena, Di Matteo, Finocchi, Geha, Goyal, Hayward, Holland, Huang, Kanariou, King, Kaplan, Kleva, Kuijpers, Lee, Lougaris, Massaad, Meyts, Morsheimer, Neven, Pai, Plebani, Prockop, Reisli, Soh, Somech, Torgerson, Kim, Walter, Gennery, Keles, Manis, Marcenaro, Moretta, Parolini and Notarangelo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 May 2017
                : 23 June 2017
                Page count
                Figures: 9, Tables: 2, Equations: 0, References: 53, Pages: 20, Words: 11783
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: 2R01AI100887, Division of Intramural Research
                Categories
                Immunology
                Original Research

                Immunology
                natural killer cells,recombinase-activating genes,non-homologous end joining,immunodeficiency,cd56,interferon-γ,degranulation

                Comments

                Comment on this article