Induction of type I interferons and viral immunity

Virus-induced type I interferons (IFNα/β) are key mediators of innate immunity and important modulators of adaptive immunity. Early recognition of virus and induction of IFNα/β 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 IFNα/β-production in murine bone marrow-derived myeloid dendritic cells (mDC). We show that both SFV and Rotavirus induce IFNα/β production via a toll-like receptor-independent pathway and IFNα/β 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 IFNα/β-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 IFNα/β 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 IFNα/β-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 IFNα/β 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 IFNα/β-signalling in the IFNR-AR1-/- mice leads to insufficient priming of T helper cells by DC. These results show that virus-induced IFNα/β can act as a potent adjuvant for antibody responses against co-administered protein antigens, but that IFNα/β 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 IFNα/β-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 IFNγ-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 IFNα/β 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.

List of scientific papers

I. Hidmark AS, McInerney GM, Nordstrom EK, Douagi I, Werner KM, Liljestrom P, Karlsson Hedestam GB. (2005). "Early alpha/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88." J Virol 79(16): 10376-85
https://pubmed.ncbi.nlm.nih.gov/16051830

II. Douagi I, McInerney GM, Hidmark AS, Miriallis V, Johansen K, Svensson L, Karlsson Hedestam GB. (2007). "Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts." J Virol. 81(6): 2758-68
https://pubmed.ncbi.nlm.nih.gov/17215281

III. Hidmark AS, Nordstrom EK, Dosenovic P, Forsell MN, Liljestrom P, Karlsson Hedestam GB. (2006). "Humoral responses against coimmunized protein antigen but not against alphavirus-encoded antigens require alpha/beta interferon signaling." J Virol. 80(14): 7100-10
https://pubmed.ncbi.nlm.nih.gov/16809315

IV. Hidmark ÅS, Douagi I, Nordström EK, Dosenovic P, Karlsson Hedestam GB. (1970). "CD8+ T cell responses against alphavirus-encoded antigens are enhanced in the absence of IFNá/â signaling." (Submitted)