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

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...

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Authors: Dobbs, Kerry; Tabellini, Giovanna; Calzoni, Enrica; Patrizi, Ornella; Martinez, Paula; Giliani, Silvia Clara; Moratto, Daniele; Al-Herz, Waleed; Cancrini, Caterina; Cowan, Morton; Bleesing, Jacob; Booth, Claire; Buchbinder, David; Burns, Siobhan O.; Chatila, Talal A.; Chou, Janet; Daza-Cajigal, Vanessa; de Bruin, Lisa M. Ott; de la Morena, Maite; Di Matteo, Gigliola; Finocchi, Andrea; Geha, Raif; Goyal, Rakesh K.; Hayward, Anthony; Holland, Steven; Huang, Chiung-Hui; Kanariou, Maria G.; King, Alejandra; Kaplan, Blanka; Kleva, Anastasiya; Kuijpers, Taco W.; Lee, Bee Wah; Lougaris, Vassilios; Massaad, Michel; Meyts, Isabelle; Morsheimer, Megan; Neven, Benedicte; Pai, Sung-Yun; Plebani, Alessandro; Prockop, Susan; Reisli, Ismail; Soh, Jian Yi; Somech, Raz; Torgerson, Troy R.; Kim, Yae-Jaen; Walter, Jolan E.; Gennery, Andrew R.; Keles, Sevgi; Manis, John P.; Marcenaro, Emanuela; Moretta, Alessandro; Parolini, Silvia; Notarangelo, Luigi D.
Format: Article
Publication date:2017
Country:España
Institution:Conselleria de Salut i Consum del Govern de les Illes Balears
Repository:Docusalut
Language:English
OAI Identifier:oai:docusalut.com:20.500.13003/9743
Online Access:https://hdl.handle.net/20.500.13003/9743
Access Level:Open access
Keyword:natural killer cells
recombinase-activating genes
non-homologous end joining
immunodeficiency
CD56
interferon-gamma
degranulation
Summary: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.

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