Significant role for IRF3 in both T cell and APC effector functions during T cell responses

Abstract

Interferon Regulatory Factor (IRF)3 is a crucial transcription factor during innate immune responses. Here we show IRF3 also has a role in adaptive T cell immune responses. Expression of IFN-γ, IL-17, and Granzyme B (GrB) during in vitro T cell responses was impaired when either dendritic cells (DCs) or T cells were derived from IRF3KO mice. Unexpectedly, IRF3–dependent NK-activating molecule (INAM), which is an NK cell activating factor of the DC innate immune response, was induced during the T cell response. Additionally, supernatants from responding T cells induced ISG54 in the RAW264.7 macrophage cell line in an IRF3 dependent manner. Moreover, addition of anti-IFN-γ prevented supernatant induction of ISG54 and recombinant IFN-γ stimulated ISG54 expression. Thus, IRF3 in APCs and T cells is required for optimal T-cell effector function and the ability of T cells to influence innate immune function of APCs.

Activation of IRF3 contributes to IFN-γ and ISG54 expression during the immune responses to B16F10 tumor growth

“…However, our data clearly show that IFN-γ synergizes with transcription factors activated by poly I:C to induce the maximal expression of ISG54 in B16 melanoma cells. In support of the data here, we recently reported that IFN-γ stimulates ISG54 expression in RAW264.7 cells and poly I:C activated IRF3 contributes to IFN-γ-stimulated expression of ISG54 [5]. ISGs are a class of molecules induced by interferons that play a significant role in limiting viral infections and whose antiviral effect includes induction of apoptosis in virus infected cells [8].…”

“…However when we added exogenous IL-12, IL-15, or IL-6 to responding T cells from IRF3KO mice, IFN-γ expression was not restored to levels found with wild-type responding T cells[19]. More recently, we showed that incubating enriched T cells from IRF3KO mice with DCs from wild-type mice during in vitro T cell responses also failed to restore IFN-γ production [5]. These unexpected findings prompted us to focus on IRF3 and T cell responses and led us to postulate that IRF3 functions intrinsically in T cell IFN-γ production during immune responses.…”

“…Expression of ISG54 was reported to be a key factor limiting growth of oral squamous cell carcinomas [11] and adenocarcinomas [12]. Moreover, expression of ISG54 depends on IRF3 [5, 10], which itself is a potent anti-viral factor [11]. Earlier reports showed that IRF3 has non-transcriptional effects.…”

“…In contrast, treatment of tumor-bearing mice or responding T cells with polyinosinic:polycytidylic (poly I:C), which activates IRF3, decreased melanoma growth and increased IFN-γ production, respectively. In addition, we unexpectedly found that IRF3 contributes intrinsically to T cell production of IFN-γ[5]. Therefore, IRF3 and compounds that activate IRF3 contribute to anti-cancer immunity by bringing about IFN-γ production from T cells.…”

“…However, IFN-γ could also induce apoptosis in theory through Interferon Stimulated Genes (ISG) like ISG54 (Aka: IFIT2) [7] [8], which is one of several tetratricopeptide repeat protein ISGs[9]. Moreover, expression of ISG54 has been shown to be dependent on activation of IRF3 [5] [10]. In addition, ISG54 is a potent anti-viral factor because it is an inducer of apoptosis [8] in virus infected cells, thus limiting viral spread.…”