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Constitutive activation of WASp leads to abnormal cytotoxic cells with increased granzyme B and degranulation response to target cells
- Source :
- JCI Insight, Vol 6, Iss 6 (2021), JCI Insight
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical investigation, 2021.
-
Abstract
- 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. ispartof: JCI INSIGHT vol:6 issue:6 ispartof: location:United States status: published
- Subjects :
- 0301 basic medicine
Lymphocyte
Immunology
NK cells
Research & Experimental Medicine
Cell Degranulation
Granzymes
03 medical and health sciences
Mice
0302 clinical medicine
Neoplasms
MHC class I
medicine
Cytotoxic T cell
Animals
Cytoskeleton
Actin
Science & Technology
biology
Chemistry
Degranulation
General Medicine
Cellular immune response
Molecular biology
Wiskott-Aldrich Syndrome
Granzyme B
030104 developmental biology
medicine.anatomical_structure
Medicine, Research & Experimental
030220 oncology & carcinogenesis
Case-Control Studies
biology.protein
Medicine
Life Sciences & Biomedicine
CD8
Wiskott-Aldrich Syndrome Protein
T-Lymphocytes, Cytotoxic
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 6
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....e56e0af168a64d3dd2e183dbb624c788