Induction of type I interferons and viral immunity

Sammanfattning: Virus-induced type I interferons (IFN?/?) are key mediators of innate immunity and important modulators of adaptive immunity. Early recognition of virus and induction of IFN?/? are important for limiting the spread of the virus. In paper I and II, we use RNA viruses, Semliki Forest virus (SFV) and Rotavirus, to investigate which viral functions and what cellular pathways are required for the induction of IFN?/?-production in murine bone marrow-derived myeloid dendritic cells (mDC). We show that both SFV and Rotavirus induce IFN?/? production via a toll-like receptor-independent pathway and IFN?/? induction in mDC by both viruses is largely dependent on IRF-3. Our data suggest that events during or downstream of viral entry, but prior to viral replication are required for the activation of IFN?/?-production in mDC. In paper III, we show that SFV provides an adjuvant effect on antibody responses against co-administered protein antigens. The adjuvant effect of SFV is abolished in mice lacking the IFN?/? receptor (IFNR-AR1-/- mice). In contrast, amplitude, longevity and composition of the antibody responses directed against virus-encoded antigens are intact in the absence of IFN?/?-signalling. Antibody responses against both the virus-encoded antigens and against co-administered antigens are also intact in MyD88-/- and TLR3-/- mice, in agreement with the observation that these mice are capable of IFN?/? induction in response to SFV. Further, we show that rSFV-induced antibody responses are dependent on T cell help and we suggest that the absence of IFN?/?-signalling in the IFNR-AR1-/- mice leads to insufficient priming of T helper cells by DC. These results show that virus-induced IFN?/? can act as a potent adjuvant for antibody responses against co-administered protein antigens, but that IFN?/? are not required for the induction of immune responses against virus-encoded antigens. In paper IV, we show that CD8+ T cell responses directed against SFV-encoded antigens are enhanced in the absence of IFN?/?-signalling. MHC class I tetramer staining demonstrated that the number of antigen-specific CD8+ T cells is lower both in blood and spleen of SFV-immunized wildtype mice compared to in SFV-immunized IFN-AR1-/- mice. The number of IFN?-producing CD8+ T cells in spleen was also lower in wildtype mice than in mice lacking the IFN-AR1. Wildtype and IFN-AR1-/- mice immunized with ex vivo-infected wildtype mouse embryonic fibroblasts cells gave similar results. These data suggest that IFN?/? signalling restricts the CD8+ T cell responses to virally encoded antigens, in contrast to its previously shown enhancing effect on cross-presentation of protein-based antigens.