AUTHOR=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 , Ott de Bruin Lisa M. , de la Morena Maite Teresa , 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 , Parvaneh Nima , 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. 

TITLE=Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content

JOURNAL=Frontiers in Immunology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00798

DOI=10.3389/fimmu.2017.00798

ISSN=1664-3224

ABSTRACT=<p>Mutations of the recombinase-activating genes 1 and 2 (<italic>RAG1</italic> and <italic>RAG2</italic>) 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 <italic>Rag<sup>−/−</sup></italic> 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 <italic>RAG</italic> 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<sup>bright</sup> CD16<sup>−/int</sup> CD57<sup>−</sup> cells, yet increased degranulation and high perforin content. Correlation was observed between <italic>in vitro</italic> recombinase activity of the mutant proteins, NK cell abnormalities, and <italic>in vivo</italic> 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.</p>