Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells.

Autor:	Kritikou JS; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Oliveira MM; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Record J; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Saeed MB; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Nigam SM; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., He M; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Keszei M; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Wagner AK; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Brauner H; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and.; Department of Medicine, Solna, Division of Rheumatology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden., Sendel A; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Sedimbi SK; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Rentouli S; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Lane DP; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Snapper SB; Gastroenterology Division, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Kärre K; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and., Vandenberghe P; Center for Human Genetics, University Hospital Leuven, Leuven, Belgium., Orange JS; Department of Pediatrics, NewYork-Presbyterian Morgan Stanley Children's Hospital, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA., Westerberg LS; Department of Microbiology Tumor and Cell Biology, Biomedicum C7, and.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2021 Mar 22; Vol. 6 (6). Date of Electronic Publication: 2021 Mar 22.
DOI:	10.1172/jci.insight.140273
Abstrakt:	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 2 patients with XLN harboring the activating WASpL270P mutation. XLN patient NK and T cells had increased granzyme B content and elevated degranulation and IFN-γ production when compared with 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 mouse T cells 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 lymphocyte function associated antigen-1 engagement. When compared with WT mice, WASpL272P mice showed reduced growth of B16 melanoma and increased capacity to reject MHC class I-deficient cells. Together, our data suggest that cytotoxic cells with constitutively active WASp have an increased capacity to respond to and kill tumor cells.
Databáze:	MEDLINE
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