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J. Biol. Chem., Vol. 277, Issue 51, 49238-49246, December 20, 2002

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

Chuan-Min Hu, So Young Jang, Jessica C. Fanzo, and Alessandra B. Pernis

From the Department of Medicine, Columbia University, New York, New York 10032

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.

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