Type I interferon-activated NK cells control polycythemia vera in vivo
Abstract
Polycythemia vera (PV) is a clonal hematopoietic stem cell (HSC) disorder resulting in overproduction of erythrocytes. While Interferon-a (IFN-a) has shown therapeutic efficacy in PV and other myeloproliferative neoplasms (MPN), its precise mechanism of action remains poorly understood. In this study, we identify natural killer (NK) cells as primary immune effectors responsive to IFN-a treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-a induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or ET undergoing IFN-a therapy, the frequency of CD56bright NK cells is increased and correlates with the molecular response. Depletion of NK cells abrogated the therapeutic effects of IFN-a. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells (HSPCs) in a TNF-a dependent manner and independent of IFN-g or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon (IFN) receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-a. This suggests that direct sensing of basal levels of type-I IFNs by NK cells is essential for attenuating disease progression, emphasizing a critical role for NK cells in immune surveillance of MPN. These findings offer new insights into type-I IFN-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.
Article Details
Authors (23)
Johanna Lossa
University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Tina M Schnöder
Hematology, Hemostasis, Oncology and Cell Therapy, Hannover Medical School (MHH), Hannover, Germany
Zora Ronge
University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Nelly Haasch
University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Katrin Hodapp
University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Federico Marini
Najla Abassi
Matthias M Gaida
University Medical Center Mainz, Mainz, Germany
Shin-Jye Lee
PharmaEssentia Corporation, Taipei, Taiwan
Alina Henrich
Michaela N Höhne-Wiechmann
TRON - Translational Oncology at the University Medical Centre of the Johannes Gutenberg University Mainz gGmbH, Mainz, Germany
Carlos Thull Mogollón
University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Kristian Schütze
University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
Matthias Klein
Tobias Bopp
Hansjörg Schild
7Research Center for Immunotherapy, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Daniel Sasca
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Carl Claudius Crodel
Klinik für Innere Medizin II Abt. Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany
Florian H Heidel
Hannover Medical School (MHH), Hannover, Germany
Steffen Koschmieder
Hans Christian Probst
University Medical Center Mainz, Mainz, Germany
Markus P Radsak
University Medical Center, Mainz, Germany
Sabine Muth
7Research Center for Immunotherapy, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany