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 Matteo & 33 others 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, 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, Alessandro Moretta, Silvia Parolini, Luigi D. Notarangelo

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (US)
Article number798
JournalFrontiers in Immunology
Volume8
Issue numberJUL
DOIs
StatePublished - Jul 17 2017

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Perforin
Recombinases
Natural Killer Cells
Phenotype
Genes
Hematopoietic Stem Cell Transplantation
Mutation
Passive Immunization
Mutant Proteins
Transplantation
Transplants

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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. / 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 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; 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.

In: Frontiers in Immunology, Vol. 8, No. JUL, 798, 17.07.2017.

Research output: Contribution to journalArticle

Dobbs, K, Tabellini, G, Calzoni, E, Patrizi, O, Martinez, P, Giliani, SC, Moratto, D, Al-Herz, W, Cancrini, C, Cowan, M, Bleesing, J, Booth, C, Buchbinder, D, Burns, SO, Chatila, TA, Chou, J, Daza-Cajigal, V, de Bruin, LMO, de la Morena, MT, Di Matteo, G, Finocchi, A, Geha, R, Goyal, RK, Hayward, A, Holland, S, Huang, CH, Kanariou, MG, King, A, Kaplan, B, Kleva, A, Kuijpers, TW, Lee, BW, Lougaris, V, Massaad, M, Meyts, I, Morsheimer, M, Neven, B, Pai, SY, Plebani, A, Prockop, S, Reisli, I, Soh, JY, Somech, R, Torgerson, TR, Kim, YJ, Walter, JE, Gennery, AR, Keles, S, Manis, JP, Marcenaro, E, Moretta, A, Parolini, S & Notarangelo, LD 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', Frontiers in Immunology, vol. 8, no. JUL, 798. https://doi.org/10.3389/fimmu.2017.00798
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 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 ; 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. / 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. In: Frontiers in Immunology. 2017 ; Vol. 8, No. JUL.
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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.",
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T1 - 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

AU - Dobbs, Kerry

AU - Tabellini, Giovanna

AU - Calzoni, Enrica

AU - Patrizi, Ornella

AU - Martinez, Paula

AU - Giliani, Silvia Clara

AU - Moratto, Daniele

AU - Al-Herz, Waleed

AU - Cancrini, Caterina

AU - Cowan, Morton

AU - Bleesing, Jacob

AU - Booth, Claire

AU - Buchbinder, David

AU - Burns, Siobhan O.

AU - Chatila, Talal A.

AU - Chou, Janet

AU - Daza-Cajigal, Vanessa

AU - de Bruin, Lisa M.Ott

AU - de la Morena, Maite Teresa

AU - Di Matteo, Gigliola

AU - Finocchi, Andrea

AU - Geha, Raif

AU - Goyal, Rakesh K.

AU - Hayward, Anthony

AU - Holland, Steven

AU - Huang, Chiung Hui

AU - Kanariou, Maria G.

AU - King, Alejandra

AU - Kaplan, Blanka

AU - Kleva, Anastasiya

AU - Kuijpers, Taco W.

AU - Lee, Bee Wah

AU - Lougaris, Vassilios

AU - Massaad, Michel

AU - Meyts, Isabelle

AU - Morsheimer, Megan

AU - Neven, Benedicte

AU - Pai, Sung Yun

AU - Plebani, Alessandro

AU - Prockop, Susan

AU - Reisli, Ismail

AU - Soh, Jian Yi

AU - Somech, Raz

AU - Torgerson, Troy R.

AU - Kim, Yae Jaen

AU - Walter, Jolan E.

AU - Gennery, Andrew R.

AU - Keles, Sevgi

AU - Manis, John P.

AU - Marcenaro, Emanuela

AU - Moretta, Alessandro

AU - Parolini, Silvia

AU - Notarangelo, Luigi D.

PY - 2017/7/17

Y1 - 2017/7/17

N2 - 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.

AB - 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.

KW - CD56

KW - Degranulation

KW - Immunodeficiency

KW - Interferon-γ

KW - Natural killer cells

KW - Non-homologous end joining

KW - Recombinase-activating genes

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DO - 10.3389/fimmu.2017.00798

M3 - Article

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JO - Frontiers in Immunology

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