Journal
JOURNAL OF IMMUNOLOGY
Volume 187, Issue 7, Pages 3721-3729Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002354
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Funding
- Wellcome Trust UK [074656/Z/04/Z]
- Medical Research Council UK [G0400197, G9536930, G0500429]
- Dorothy Hodgkin postgraduate award
- Medical Research Council Centre for Transplantation
- Department of Health via the National Institute for Health Research Comprehensive Biomedical Research Centre
- King's College London
- King's College Hospital National Health Service Foundation Trust
- MRC [G0500429, G9536930, G0600081, G0900950, G9721629, G0400197] Funding Source: UKRI
- Medical Research Council [G1000758, G1000758B, G9536930, G0900950B, G0500429, G9721629B, G0400197, G0600081, G9721629, G0900950] Funding Source: researchfish
- National Institute for Health Research [CL-2008-17-003, NF-SI-0508-10212] Funding Source: researchfish
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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. The Journal of Immunology, 2011, 187: 3721-3729.
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