Type I interferons (IFNs), predominantly IFN-␣ and -, play critical roles in both innate and adaptive immune responses against viral infections. Interferon regulatory factor 7 (IRF7), a key innate immune molecule in the type I IFN signaling pathway, is essential for the type I IFN response to many viruses, including lymphocytic choriomeningitis virus (LCMV). Here, we show that although IRF7 knockout (KO) mice failed to control the replication of LCMV in the early stages of infection, they were capable of clearing LCMV infection. Despite the lack of type I IFN production, IRF7 KO mice generated normal CD4 ؉ T cell responses, and the expansion of naïve CD8 ؉ T cells into primary CD8 ؉ T cells specific for LCMV GP 33-41 was relatively normal. In contrast, the expansion of the LCMV NP 396 -specific CD8 ؉ T cells was severely impaired in IRF7 KO mice. We demonstrated that this defective CD8؉ T cell response is due neither to an impaired antigen-presenting system nor to any intrinsic role of IRF7 in CD8 ؉ T cells. The lack of a type I IFN response in IRF7 KO mice did not affect the formation of memory CD8 ؉ T cells. Thus, the present study provides new insight into the impact of the innate immune system on viral pathogenesis and demonstrates the critical contribution of innate immunity in controlling virus replication in the early stages of infection, which may shape the quality of CD8 ؉ T cell responses.
Induction of type I interferons (IFNs) is not only essential for host innate immunity against viral pathogens but also critically involved in the development of virus-specific adaptive immune responses, in particular, T cell responses. Activation of naïve T cells occurs through three signals: the peptide-major histocompatibility complex (MHC) (signal 1), costimulatory molecules on antigen-presenting cells (APCs) (signal 2), and immunoregulatory cytokines (signal 3) (16). Type I IFNs are involved in regulating all three signals and can also directly act on T cells by interacting with the IFN-␣/ receptor on T cells to provide survival signals (7,26,29,31). In addition, in vitro studies have shown that IFN-␣ coordinately regulates lymphocytic choriomeningitis virus (LCMV)-specific CD8 ϩ T cell activation (38, 41). Studies suggest that type I IFN production is controlled by a group of transcriptional factors, including nuclear factor B (NF-B) and the interferon regulatory factors (IRFs) (19,21). Nine IRFs have been identified to date, and IRF3 and its close relative IRF7 are important in controlling the induction of type I IFNs during viral infections (20,22,50). IRF7 expression is restricted to certain cell types, such as B cells and dendritic cells (DCs) (42). In other cells, IRF7 expression is inducible in response to type I IFNs as well as viral infections (42, 50). IRF7 is localized in the cytoplasm in an inactive form. Once activated, IRF7 undergoes phosphorylation and translocation to the nucleus to induce expression of the genes responsible for the production of type I IFNs (50, 53). We, and others, demonstrate...