Beyond Innate Immunity: Defining a Role for Interferon Regulatory Factor 3 in CD4+ T Cell Responses

Interferon regulatory factor 3 (IRF3) is a transcription factor found in the cytoplasm of most nucleated cells. Upon pathogen detection by pattern recognition receptors, IRF3 becomes activated and translocates to the nucleus where it mediates the production of type I interferon (IFN) and IFN-stimulated genes. The collective actions of these genes induce an antimicrobial state within infected and neighboring cells, allowing for pathogen clearance. Whereas the type I IFN system has been studied extensively in the context of pathogen responses, it has more recently become appreciated for its role in immune cell modulation. In this report we discuss novel findings highlighting the involvement of the type I IFN system—with a focus on IRF3—in T cell development, activation, differentiation, and cytokine production.Using a combination of in vitro assays and in vivo disease models, we demonstrate that IRF3 is a positive regulator of lL-17 and IFN-γ in CD4+ T cells. We show that IRF3-deficient CD4+ T cells have impaired production of the pro-inflammatory cytokines IL-17 and IFN-γ, and are unable to induce disease in the T cell transfer model of colitis. Unexpectedly, we observed IRF3 nuclear translocation in activated T cells. To our knowledge, this is the first description of IRF3 activation following T cell receptor stimulation. These results, which are the focus of chapter 1, reveal a previously unappreciated role for IRF3 in CD4+ T cell responses and extend its role beyond the innate immune response to pathogens.Additionally, we show that type I IFN limits T cell production of IL-2—a cytokine required for T cell activation and expansion—by indirectly altering histone modifications in the IL-2 promoter to retain the locus in an inaccessible configuration. These results, which are the focus of chapter 2, help explain why type I IFN has been an effective treatment for multiple sclerosis—a T cell- mediated autoimmune condition