Role of Interferon Regulatory Factor 7 in T Cell Responses during Acute Lymphocytic Choriomeningitis Virus Infection

Abstract

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...

IRF7-Dependent Type I Interferon Production Induces Lethal Immune-Mediated Disease in STAT1 Knockout Mice Infected with Lymphocytic Choriomeningitis Virus

“…While the development of the lethal disease following LCMV infection in STAT1 KO mice does not require IFN-␥ (17), the biological significance of IFN-I signaling in this process was not known but should be considered, since there is now abundant evidence that IFN-I can mediate many biological functions independently of STAT1 (37). IRF7 is a key transcriptional regulator of IFN-I production during LCMV infection (24)(25)(26)(27) that, interestingly, is sig- nificantly induced in a STAT1-independent fashion in the spleen and central nervous system during LCMV infection (28). Due to these considerations, here we initially studied the role of IRF7 in the lethal host response induced by LCMV in STAT1 KO mice by generating STAT1/IRF7 DKO mice.…”

“…Thus, the induction of IFN-Is following LCMV infection is mediated via TLR7/9 or RIG-I/MDA5 (21,22) and is dependent on IRF7, but not IRF3 (23). While IRF3 is dispensable for the induction of IFN-I during LCMV infection (24), IRF7 is obligatorily required for the production of IFN-␣ but is only partially required for the production of IFN-␤ (24)(25)(26). Consistent with this role of IRF7, IRF7 KO mice are defective in the initial control of LCMV infection and spread but not the subsequent generation of CD8 ϩ antiviral T cells that promote the clearance of infection (25)(26)(27).…”

Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis

“…In the cytoplasm IRF7 is associated with MyD88, TRAF6 and IKK and can be activated through both TLR engagement and MyD88-independent viral signalling pathways [29]. IRF7 is not only important for the induction of a subset of IFNa genes [15], but also for the expression of several mitochondrial and DNA repair genes and the generation of the anti-viral effector CD8 + T cell repertoire [77,78]. Importantly, IRF7 also negatively regulates NF-kB signalling by binding IkBb [79,80].…”

Anti-viral CD8 T cells and the cytokines that they love

“…Nevertheless, modulating the inflammatory milieu can be disastrous for viral control. Blockade of IFNα/β during the priming phase of LCMV Armstrong infection results in failure to clear the virus (Sandberg et al, 1994) and, similarly, IFNAR-deficient ( −/− ) mice poorly control the low virulence VV strain Lancy or LCMV Armstrong or WE (Muller et al, 1994; van den Broek et al, 1995; Zhou et al, 2012). Infection of IFNAR −/− mice with more persistent strains of LCMV, such as LCMV Docile or clone 13, results in a high titer life-long infection and exacerbated T cell exhaustion (Ou et al, 2001), as opposed to the slowly controlled persistent infection observed in wild type mice.…”