Constitutive WASp activation leads to abnormal cytotoxic cells with increased response against tumors

Joanna S. Kritikou; Mariana M.S. Oliveira; Julien Record; Mezida B. Saeed; Saket M. Nigam; Minghui He; Marton Keszei; Arnika K. Wagner; Hanna Brauner; Anton Sendel; Saikiran K. Sedimbi; Stamatina Rentouli; David P. Lane; Scott B. Snapper; Klas Kärre; Peter Vandenberghe; Jordan S. Orange; Lisa S. Westerberg

doi:10.1172/jci.insight.140273

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Kritikou, J. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Oliveira, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Record, J. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Saeed, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Nigam, S. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by He, M. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Keszei, M. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Wagner, A. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Brauner, H. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Sendel, A. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Sedimbi, S. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Rentouli, S. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Lane, D. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Snapper, S. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Kärre, K. in: JCI | PubMed | Google Scholar

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Vandenberghe, P. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Orange, J. in: JCI | PubMed | Google Scholar |

¹Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, United States of America

⁴Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

⁵Department of Pediatrics, Vagelos College of Physicians and Surgeons, New York, United States of America

Find articles by Westerberg, L. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.140273.
Copyright © 2021, Kritikou et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published February 23, 2021 - Version history

X-linked neutropenia (XLN) is caused by gain-of-function mutations in the actin regulator Wiskott-Aldrich Syndrome protein (WASp). XLN patients have reduced numbers of cytotoxic cells in peripheral blood, however, their capacity to kill tumor cells remains to be determined. Here, we examined NK and T cells from two XLN patients harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased Granzyme B content and elevated degranulation and IFNγ production when compared to healthy control cells. Murine WASpL272P NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28 coated beads, respectively. WASpL272P T cells mice had normal degranulation and cytokine response whereas WASpL272P NK cells showed an enhanced response. Imaging experiments revealed that while WASpL272P CD8 T cells had increased accumulation of actin upon TCR activation, WASpL272P NK cells had normal actin accumulation at lytic synapses triggered through NKp46 signaling but had impaired response to LFA-1 engagement. When compared to WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggests that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.

Version 1 (February 23, 2021): In-Press Preview

Constitutive WASp activation leads to abnormal cytotoxic cells with increased response against tumors

Article tools

Metrics

Go to

Constitutive WASp activation leads to abnormal cytotoxic cells with increased response against tumors

Article tools

Metrics

Go to

Sign up for email alerts