Frontiers in Immunology (Jul 2017)
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,
- Caterina Cancrini,
- Morton Cowan,
- Jacob Bleesing,
- Claire Booth,
- David Buchbinder,
- Siobhan O. Burns,
- Siobhan O. Burns,
- Talal A. Chatila,
- Janet Chou,
- Vanessa Daza-Cajigal,
- Lisa M. Ott de Bruin,
- Maite Teresa de la Morena,
- Gigliola Di Matteo,
- Gigliola Di Matteo,
- Andrea Finocchi,
- Andrea 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,
- Nima Parvaneh,
- Nima Parvaneh,
- Alessandro Plebani,
- Susan Prockop,
- Ismail Reisli,
- Jian Yi Soh,
- Raz Somech,
- Troy R. Torgerson,
- Yae-Jaen Kim,
- Jolan E. Walter,
- Andrew R. Gennery,
- Andrew R. Gennery,
- Sevgi Keles,
- John P. Manis,
- Emanuela Marcenaro,
- Alessandro Moretta,
- Silvia Parolini,
- Luigi D. Notarangelo
Affiliations
- Kerry Dobbs
- Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Giovanna Tabellini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Enrica Calzoni
- “A. Nocivelli Institute for Molecular Medicine”, Pediatric Clinic, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy
- Ornella Patrizi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Paula Martinez
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
- Silvia Clara Giliani
- “A. Nocivelli Institute for Molecular Medicine”, Pediatric Clinic, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy
- Daniele Moratto
- “A. Nocivelli Institute for Molecular Medicine”, Pediatric Clinic, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Brescia, Italy
- Waleed Al-Herz
- Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
- Caterina Cancrini
- DPUO, Division of Immuno-Infectivology, University Department of Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy
- Caterina Cancrini
- School of Medicine, University of Tor Vergata, Rome, Italy
- Morton Cowan
- Pediatric Allergy Immunology and Blood and Marrow Transplant Division, University of California, San Francisco, Benioff Children’s Hospital, San Francisco, CA, United States
- Jacob Bleesing
- Division of Hematology/Oncology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
- Claire Booth
- 0Institute for Immunity and Transplantation, University College London, London, United Kingdom
- David Buchbinder
- 1Division of Pediatric Hematology, Children’s Hospital Orange County, University of California Irvine, Orange County, CA, United States
- Siobhan O. Burns
- 0Institute for Immunity and Transplantation, University College London, London, United Kingdom
- Siobhan O. Burns
- 2Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom
- Talal A. Chatila
- 3Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- Janet Chou
- 3Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- Vanessa Daza-Cajigal
- 0Institute for Immunity and Transplantation, University College London, London, United Kingdom
- Lisa M. Ott de Bruin
- 3Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- Maite Teresa de la Morena
- 4Division of Allergy and Immunology, Southwestern Medical Center, University of Texas, Dallas, TX, United States
- Gigliola Di Matteo
- DPUO, Division of Immuno-Infectivology, University Department of Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy
- Gigliola Di Matteo
- School of Medicine, University of Tor Vergata, Rome, Italy
- Andrea Finocchi
- DPUO, Division of Immuno-Infectivology, University Department of Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy
- Andrea Finocchi
- School of Medicine, University of Tor Vergata, Rome, Italy
- Raif Geha
- 3Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- Rakesh K. Goyal
- 5Division of Hematology/Oncology/BMT, Children’s Mercy Hospital & Clinics, Kansas City, MO, United States
- Anthony Hayward
- 6Department of Pediatrics, Brown University, Providence, RI, United States
- Steven Holland
- 7Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- Chiung-Hui Huang
- 8Department of Paediatrics, National University Hospital, Singapore, Singapore
- Maria G. Kanariou
- 9Department of Immunology-Histocompatibility, “Aghia Sophia” Children’s Hospital, Athens, Greece
- Alejandra King
- 0Division of Pediatric Immunology, Hospital Luis Calvo Mackenna, Santiago, Chile
- Blanka Kaplan
- 1Department of Pediatrics, Division of Allergy and Immunology, Hofstra Northwell School of Medicine, Hofstra University, Great Neck, NY, United States
- Anastasiya Kleva
- 1Department of Pediatrics, Division of Allergy and Immunology, Hofstra Northwell School of Medicine, Hofstra University, Great Neck, NY, United States
- Taco W. Kuijpers
- 2Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children’s Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands
- Bee Wah Lee
- 8Department of Paediatrics, National University Hospital, Singapore, Singapore
- Vassilios Lougaris
- 3Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy
- Michel Massaad
- 3Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
- Isabelle Meyts
- 4Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- Megan Morsheimer
- 5Transplantation Branch, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
- Benedicte Neven
- 6Pediatric Hematology-Immunology Department, Hospital Necker-Enfants Malades, Institute Imagine, AP-HP, Paris Descartes University, Sorbonne-Paris-Cité, Paris, France
- Sung-Yun Pai
- 7Division of Hematology-Oncology, Boston Children’s Hospital, Boston, MA, United States
- Nima Parvaneh
- 8Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
- Nima Parvaneh
- 9Research Center for Immunodeficiencies, Children’s Medical Center, Tehran, Iran
- Alessandro Plebani
- 3Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy
- Susan Prockop
- 0Bone Marrow Transplant Service, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- Ismail Reisli
- 1Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
- Jian Yi Soh
- 8Department of Paediatrics, National University Hospital, Singapore, Singapore
- Raz Somech
- 2Pediatric 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
- Troy R. Torgerson
- 3Department of Pediatrics and Immunology, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
- Yae-Jaen Kim
- 4Division of Infectious Diseases and Immunodeficiency, Department of Pediatrics, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, South Korea
- Jolan E. Walter
- 5Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
- Andrew R. Gennery
- 6Department of Paediatric Immunology, Great North Children’s Hospital, Newcastle Upon Tyne, United Kingdom
- Andrew R. Gennery
- 7Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom
- Sevgi Keles
- 1Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
- John P. Manis
- 8Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, United States
- Emanuela Marcenaro
- 9Molecular Immunology Laboratories, Department of Experimental Medicine, University of Genoa, Genoa, Italy
- Alessandro Moretta
- 9Molecular Immunology Laboratories, Department of Experimental Medicine, University of Genoa, Genoa, Italy
- Silvia Parolini
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
- Luigi D. Notarangelo
- Laboratory of Host Defenses, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
- DOI
- https://doi.org/10.3389/fimmu.2017.00798
- Journal volume & issue
-
Vol. 8
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.
Keywords
- natural killer cells
- recombinase-activating genes
- non-homologous end joining
- immunodeficiency
- CD56
- interferon-γ
