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

Kerry Dobbs, Giovanna Tabellini, Enrica Calzoni, Ornella Patrizi, Paula Martinez, Silvia Clara Giliani, Daniele Moratto, Waleed Al-Herz, Caterina Cancrini, Morton Cowan, Jacob Bleesing, Claire Booth, David Buchbinder, Siobhan O. Burns, Talal A. Chatila, Janet Chou, Vanessa Daza-Cajigal, Lisa M.Ott de Bruin, Maite Teresa de la Morena, Gigliola Di MatteoAndrea Finocchi, Raif Geha, Rakesh K. Goyal, Anthony Hayward, Steven Holland, Chiung Hui Huang, Maria G. Kanariou, Alejandra King, Blanka Kaplan, Anastasiya Kleva, Taco W. Kuijpers, Bee Wah Lee, Vassilios Lougaris, Michel Massaad, Isabelle Meyts, Megan Morsheimer, Benedicte Neven, Sung Yun Pai, Alessandro Plebani, Susan Prockop, Ismail Reisli, Jian Yi Soh, Raz Somech, Troy R. Torgerson, Yae Jaen Kim, Jolan E. Walter, Andrew R. Gennery, Sevgi Keles, John P. Manis, Emanuela Marcenaro

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number798
JournalFrontiers in Immunology
Volume8
Issue numberJUL
DOIs
Publication statusPublished - Jul 17 2017

Keywords

  • CD56
  • Degranulation
  • Immunodeficiency
  • Interferon-γ
  • Natural killer cells
  • Non-homologous end joining
  • Recombinase-activating genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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