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

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 WASp(L270P) 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 WASp(L272P) NK and T cells formed stable synapses with YAC-1 tumor cells and anti-CD3/CD28–coated beads, respectively. WASp(L272P) mouse T cells had normal degranulation and cytokine response whereas WASp(L272P) NK cells showed an enhanced response. Imaging experiments revealed that while WASp(L272P) CD8(+) T cells had increased accumulation of actin upon TCR activation, WASp(L272P) 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, WASp(L272P) 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.