Type-I interferon-activated NK cells control polycythemia vera in vivo.
Key claim: Type-I interferon controls polycythemia vera by activating NK cells that preferentially kill JAK2V617F-mutant hematopoietic stem and progenitor cells in a TNF-α-dependent manner and provide ongoing immune surveillance of MPN.
Abstract
Polycythemia vera (PV) is a clonal hematopoietic stem cell disorder resulting in overproduction of erythrocytes. Although interferon alfa (IFN-α) 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-α treatment in PV essential for disease control in vivo. Using a transgenic mouse model of PV, we demonstrate that IFN-α induces the expansion of CD27+ NK cells in the bone marrow. In patients with PV or essential thrombocythemia undergoing IFN-α 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-α. In vitro experiments demonstrate that NK cells preferentially killed Jak2VF mutant hematopoietic stem and progenitor cells in a tumor necrosis factor-α-dependent manner and independent of IFN-γ or NKG2D. Notably, PV mice depleted of NK cells or lacking type-I interferon receptor on NK cells showed accelerated disease progression in the absence of exogenous IFN-α. This suggests that direct sensing of basal levels of type-I interferons 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 interferon-mediated immune modulation in MPN and highlight the potential of NK cell activation to improve therapeutic outcomes.
Why this matters
Interferon-α is the most disease-modifying therapy in PV, yet its mechanism of malignant-clone targeting has been unresolved — a gap explicitly flagged in this area’s prior IFN-mechanism review. Identifying NK cells as the primary IFN effector and showing TNF-α-dependent preferential killing of JAK2V617F HSPCs reframes PV as an immune-surveilled disease and predicts differential IFN responsiveness by JAK2 allele burden across PV vs JAK2-mutated ET. It also opens NK-directed immunotherapy and TNF-axis modulation as new subtype-specific therapeutic angles.