title: IL-2 regulates expression of C-MAF in human CD4 T cells.
abstract: Blockade of IL-2R with humanized anti-CD25 Abs, such as daclizumab, inhibits Th2 responses in human T cells. Recent murine studies have shown that IL-2 also plays a significant role in regulating Th2 cell differentiation by activated STAT5. To explore the role of activated STAT5 in the Th2 differentiation of primary human T cells, we studied the mechanisms underlying IL-2 regulation of C-MAF expression. Chromatin immunoprecipitation studies revealed that IL-2 induced STAT5 binding to specific sites in the C-MAF promoter. These sites corresponded to regions enriched for markers of chromatin architectural features in both resting CD4 and differentiated Th2 cells. Unlike IL-6, IL-2 induced C-MAF expression in CD4 T cells with or without prior TCR stimulation. TCR-induced C-MAF expression was significantly inhibited by treatment with daclizumab or a JAK3 inhibitor, R333. Furthermore, IL-2 and IL-6 synergistically induced C-MAF expression in TCR-activated T cells, suggesting functional cooperation between these cytokines. Finally, both TCR-induced early IL4 mRNA expression and IL-4 cytokine expression in differentiated Th2 cells were significantly inhibited by IL-2R blockade. Thus, our findings demonstrate the importance of IL-2 in Th2 differentiation in human T cells and support the notion that IL-2R-directed therapies may have utility in the treatment of allergic disorders.
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, United Kingdom.
authors.forename: Aradhana
authors.initials: A
authors.lastname: Rani
authors.forename: Behdad
authors.initials: B
authors.lastname: Afzali
authors.forename: Audrey
authors.initials: A
authors.lastname: Kelly
authors.forename: Lemlem
authors.initials: L
authors.lastname: Tewolde-Berhan
authors.forename: Mark
authors.initials: M
authors.lastname: Hackett
authors.forename: Aditi S
authors.initials: AS
authors.lastname: Kanhere
authors.forename: Isabela
authors.initials: I
authors.lastname: Pedroza-Pacheco
authors.forename: Holly
authors.initials: H
authors.lastname: Bowen
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jenner
authors.forename: David J
authors.initials: DJ
authors.lastname: Cousins
authors.forename: Jack A
authors.initials: JA
authors.lastname: Ragheb
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.forename: Susan
authors.initials: S
authors.lastname: John
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002469:Cell Separation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051257:Proto-Oncogene Proteins c-maf / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; C495607:MAF protein, human; D051257:Proto-Oncogene Proteins c-maf; D050799:STAT5 Transcription Factor