RT Journal Article
SR Electronic
T1 Ruxolitinib partially reverses functional NK cell deficiency in patients with <em>STAT1</em> gain-of-function mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 157271
DO 10.1101/157271
A1 Alexander Vargas-Hernandez
A1 Emily M. Mace
A1 Ofer Zimmerman
A1 Christa S. Zerbe
A1 Alexandra F. Freeman
A1 Sergio Rosenzweig
A1 Jennifer W. Leiding
A1 Troy Torgerson
A1 Matthew C. Altman
A1 Edith Schussler
A1 Charlotte Cunningham-Rundles
A1 Ivan K. Chinn
A1 Imelda C. Hanson
A1 Nicholas L. Rider
A1 Steven M. Holland
A1 Jordan S. Orange
A1 Lisa R. Forbes
YR 2017
UL http://biorxiv.org/content/early/2017/06/28/157271.abstract
AB Background Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility.Objective We sought to investigate NK cell function in STAT1 GOF patients. Methods: NK cell phenotype and function were determined in 16 STAT1 GOF patients.Methods NK cell phenotype and function were determined in 16 STAT1 GOF patients.NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib.Results Peripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function.Conclusions Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.