O003 Interferon alpha subtype 11 activates NK cells and enables control of retroviral infection

Introduction Type I Interferons (IFNs) are a multigene family with up to 14 different IFNα subtypes. IFNs have direct anti-viral activity mediated by the induction of anti-viral enzymes, but they also stimulate cells of the innate and adaptive immune system. Various studies demonstrated distinct anti-viral activities of specific IFNα subtypes but their immunomodulatory properties during viral infections have not been investigated. The innate immune response mediated by cells such as natural killer (NK) cells is critical for the rapid containment of virus replication and spread during acute infection. In this study we are interested on the specific immunomodulatory effects of various IFNα subtypes on NK cell functions during retroviral infections. Methods We used different IFNα subtypes for immunotherapy of acute Friend retrovirus (FV) infection in mice to study their immunomodulatory effects in vivo . For that purpose, we did FACS analysis of different lymphocyte populations, analysis of viral loads, cell depletion experiments, adoptive transfer and in vitro cytotoxicity assays. Result Treatment of mice with IFNα11 during FV infection significantly reduced viral loads and resulted in long-term protection from virus-induced leukemia. The effect of IFNα11 on NK cells was direct and signaled through the type I IFN receptor. Furthermore, IFNα11-mediated activation of NK cells enabled cytolytic killing of FV-infected target cells via the exocytosis pathway. Depletion and adoptive transfer experiments illustrated that NK cells played a major role in successful IFNα11 therapy. Additional experiments with Mouse Cytomegalovirus infections demonstrated that the therapeutic effect of IFNα11 is not restricted to retroviruses. The type I IFN subtypes 2 and 5, which bind the same receptor as IFNα11, did not elicit similar antiviral effects. These results demonstrate a unique and subtype-specific activation of NK cells by IFNα11.