Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression

Claudia Ribeiro de Almeida, HE (Helen Elizabeth) Heath, S (Sanja) Krpic, Gemma Dingjan, Jan piet Hamburg, Ingrid Bergen, S (Suzanne) van de Nobelen, Frank Sleutels, Frank Grosveld, Niels Galjart, Rudi Hendriks

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Differentiation of naive CD4(+) cells into Th2 cells is accompanied by chromatin remodeling at the Th2 cytokine focus allowing the expression of the IL-4, IL-5, and IL-13 genes. In this report, we investigated the role in Th2 differentiation of the transcription regulator CCCTC-binding factor (CTCF). Chromatin immunoprecipitation analysis revealed multiple CTCF binding sites in the Th2 cytokine locus. Conditional deletion of the Ctef gene in double-positive thymocytes allowed development of peripheral T cells, but their activation and proliferation upon anti-CD3/anti-CD28 stimulation in vitro was severely impaired. Nevertheless, when TCR signaling was circumvented with phorbol ester and ionomycin, we observed proliferation of CTCF-deficient T cells, enabling the analysis of Th2 differentiation in vitro. We found that in CTCF-deficient Th2 polarization cultures, transcription of IL-4, IL-5, and IL-13 was strongly reduced. By contrast, CTCF deficiency had a moderate effect on IFN-gamma production in Th1 cultures and IL-17 production in Th17 cultures was unaffected. Consistent with a Th2 cytokine defect, CTCF-deficient mice had very low levels of IgG1 and IgE in their serum, but IgG2c was close to normal. In CTCF-deficient Th2 cultures, cells were polarized toward the Th2 lineage, as substantiated by induction of the key transcriptional regulators GATA3 and special AT-rich binding protein I (SATB1) and down-regulation of T-bet. Also, STAT4 expression was low, indicating that in the absence of CTCF, GATA3 still operated as a negative regulator of STAT4. Taken together, these findings show that CTCF is essential for GATAX and SATB1-dependent regulation of Th2 cytokine gene expression. The Journal of Immunology, 2009, 182: 999-1010.
Original languageUndefined/Unknown
Pages (from-to)999-1010
Number of pages12
JournalJournal of Immunology
Issue number2
Publication statusPublished - 2009

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