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Open Access | 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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Published February 23, 2021 - More info
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.