| Popis: |
Type I interferons (IFN-Is) are master regulators of the immune system. They are responsible for initiating the antiviral response but also have immunomodulatory effects on cells of the innate and adaptive immune system. Despite being critical for cellular responses to IFN-I, the role of the transcription factor interferon regulatory factor 9 (IRF9) is rarely studied. Using the murine model of lymphocytic choriomeningitis virus (LCMV) infection, this project aimed to clarify the role of IRF9-dependent IFN-I signalling during viral infection. In immunocompetent mice, infection with the Armstrong strain of LCMV causes a transient infection and CD8+ T cell mediated virus clearance. By contrast, absence of the IFN-I receptor IFNAR, or IRF9, resulted in virus spread and persistence. This was accompanied by an exhausted antiviral CD8+ T cell response. Our results further showed that PDL1, a cell surface molecule critical in mediating T cell exhaustion, was required for the survival of IFNAR- and IRF9-defcient mice following LCMV infection. Although, CD8+ T cells mediated a lethal disease in the absence of PDL1, they maintained an exhausted phenotype, suggesting that alternative mechanisms that are regulated by PDL1 contribute to disease. Similarly, during persistent infection of IFNAR- and IRF9-deficient mice, neutralisation of PDL1 enhanced antiviral responses to LCMV, but there was no apparent reactivation of the CD8+ T cell response. In summary, our findings demonstrate that IRF9-dependent IFN-I signalling is required for an effective CD8+ T cell response to LCMV. Persistent infection and survival of mice in the absence of IFNAR or IRF9 is dependent on the PD1/PDL1 pathway inhibiting a detrimental CD8+ T cell response. This has broader implications for elucidating the immunomodulatory effects of IFN-Is in mediating T cell responses during infection, contributing to our understanding of immunotherapeutic strategies, whose molecular mechanisms remain largely unknown. |
