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

• DOI: 10.1172/jci.insight.140273
• Publication Date: 2021-02-28T01:44:31Z
• Authors: Joanna S. Kritikou; Mariana M.S. Oliv...; Julien Record; Mezida B. Saeed; Saket M. Nigam; Minghui He; Marton Keszei; Arnika K. Wagner; Hanna Brauner; Anton Sendel; Saikiran K. Sedimbi; Stamatina Rentouli; David P. Lane; Scott B. Snapper; Klas Kärre; Peter Vandenberghe; Jordan S. Orange; Lisa S. Westerberg
• Keywords: Granzyme

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 peripheral blood; however, their capacity to kill tumor remains be determined. Here, we examined NK and T from 2 with harboring activating WASpL270P mutation. patient had increased granzyme B content elevated degranulation IFN-γ production when compared healthy control cells. Murine WASpL272P formed stable synapses YAC-1 anti-CD3/CD28-coated beads, respectively. mouse normal cytokine response whereas showed an enhanced response. Imaging experiments revealed that while CD8+ accumulation upon TCR activation, at lytic triggered through NKp46 signaling but impaired lymphocyte function associated antigen-1 engagement. When WT mice, mice growth B16 melanoma reject MHC class I-deficient Together, our data suggest constitutively active WASp respond