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.