Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4

Abstract

Production of cytokines is one of the major mechanisms employed by CD4؉ T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4؉ T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

Enhancer-Mediated Control of Macrophage-Specific Arginase I Expression

“…However, transfection experiments failed to confirm any role for this factor in arginase I regulation (data not shown). IRF-4 was appealing because it forms a complex with PU.1 that is understood in atomic detail (30), and plays an important role in regulating IL-4 responses (31)(32)(33)(34). However, macrophages from IRF-4 Ϫ/Ϫ mice had completely normal IL-4-mediated induction of arginase I (data not shown).…”

Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naïve vs. effector/memory CD4+T cells

“…Rengarajan et al (19) described that IRF-4 physically interacts with NFATc2 and enhances transcriptional activation of the IL-4 promoter. In human studies, Hu et al (27) reported that stable expression of IRF-4 in the Jurkat human T cell line led to production of Th2 cytokines and that IRF-4 binds the IL-4 promoter element triggering the transcription of IL-4. These studies used immortalized cells, which may represent effector/memory cell types, to evaluate the effect of IRF-4 on IL-4 production, and they are consistent with our observation that IRF-4 Ϫ/Ϫ CD4 ϩ T cells are defective in Th2 development and that IL-4 production by effector/memory IRF-4 Ϫ/Ϫ CD4 ϩ T cells is much lower than BALB/c CD4 ϩ T cells.…”

Nuclear factor of activated T cells negatively regulates expression of the tumor necrosis factor receptor-related 2 gene in T cells

“…NFATc2 downregulates cyclin-dependent kinase 4 (CDK4) by directly binding and repressing its transcription through the recruitment of histone deacetylase (Baksh et al, 2002). NFATs act synergistically with other proteins (Lim et al 2008) such as AP-1 (Wisniewska et al, 2007), and IRF (Hu et al, 2002). Although we have reported that IRF molecules are involved in TR2 regulation (Sul et al, 2008), the interaction of NFATs with other proteins, and the precise mechanism of regulation of TR2 gene expression, require further investigated.…”