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.
Highlights
Natural killer (NK) cells integrate signals from the environment by forming two types of immunological synapses; one inhibitory synapse mediated by inhibitory receptors and one activating lytic synapse meditated by activating receptors[15]
We found that WASp KO NK cells developed normally but had increased expression of DNAM-1, KLRG1, and LAG-3
This data suggested that WASp KO NK cells failed to reject hematopoietic grafts lacking MHC class I molecules
Summary
NK cells integrate signals from the environment by forming two types of immunological synapses; one inhibitory synapse mediated by inhibitory receptors and one activating lytic synapse meditated by activating receptors[15]. The cytolytic defect of WAS patient NK cells can be rescued by addition of exogenous IL-217,25 that induces phosphorylation of WAVE2 and actin polymerization[17]. This has prompted initiation of clinical trials for IL-2 treatment of WAS patients as described for the first treated patient[17]. The outcome of IL-2 treatment for NK cell-mediated killing of lymphoreticular tumors, including lymphomas that is a major cause of death in WAS patients, remains unknown. WASp KO NK cells had decreased formation of immune synapses with lymphoma target cells and reduced killing capacity of MHC class I negative hematopoietic grafts in vivo. In cohorts of neuroblastoma patients and patients with diffuse large B cell lymphoma we identified a strong correlation between WASp, IL-2, and patient survival
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