Modulation of T cell cytokine production by interferon regulatory factor-4.
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.
Hu
Chuan-Min
CM
Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Jang
So Young
SY
Fanzo
Jessica C
JC
Pernis
Alessandra B
AB
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D019070:Cell Lineage; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors; D016753:Interleukin-10 / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009841:Oligonucleotides / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D000099218:Interferon Regulatory Factor-4
D016207:Cytokines; D004247:DNA; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D018793:Interleukin-13; D007376:Interleukin-2; D015847:Interleukin-4; D008156:Luciferases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009841:Oligonucleotides; D012333:RNA, Messenger; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse