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IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.
- Source :
-
Scientific reports [Sci Rep] 2016 Aug 01; Vol. 6, pp. 30636. Date of Electronic Publication: 2016 Aug 01. - Publication Year :
- 2016
-
Abstract
- To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival.
- Subjects :
- Animals
Antigens, Differentiation, T-Lymphocyte analysis
CD56 Antigen analysis
Cell Degranulation
Cytotoxicity, Immunologic
Humans
Interferon-gamma metabolism
Killer Cells, Natural chemistry
Lymphoma mortality
Lymphoma pathology
Mice, Inbred BALB C
Mice, Inbred C57BL
Survival Analysis
Antineoplastic Agents metabolism
Interleukin-2 metabolism
Killer Cells, Natural immunology
Lymphoma immunology
Tumor Microenvironment immunology
Wiskott-Aldrich Syndrome Protein deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 27477778
- Full Text :
- https://doi.org/10.1038/srep30636