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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

Dobbs, K; Tabellini, G; Calzoni, E; Patrizi, O; Martinez, P; Giliani, SC; Moratto, D; ... Notarangelo, LD; + view all (2017) 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. Frontiers In Immunology , 8 , Article 798. 10.3389/fimmu.2017.00798. Green open access

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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 CD56bright 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.

Type: Article
Title: 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
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2017.00798
Publisher version: https://doi.org/10.3389/fimmu.2017.00798
Language: English
Additional information: © 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.
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, Natural Killer Cells, Recombinase-Activating Genes, Non-Homologous End Joining, Immunodeficiency, Cd56, Interferon-Gamma, Degranulation, Human NK Cells, Severe Combined Immunodeficiency, Human Cytomegalovirus-Infection, Rag Mutations, Functional-Heterogeneity, Omenn-Syndrome, Cmv Infection, Bone-Marrow, T-Cells, In-Vivo
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1568125
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