STAT4 and T-bet are required for the plasticity of IFN-γ expression across Th2 ontogeny and influence changes in Ifng promoter DNA methylation.

Williams CL, Schilling MM, Cho SH, Lee K, Wei M, Aditi , Boothby M
J Immunol. 2013 191 (2): 678-87

PMID: 23761633 · PMCID: PMC3702659 · DOI:10.4049/jimmunol.1203360

CD4(+) T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN- γ. IL-4-producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to production of IFN-γ along with IL-4 in the same cell. We now show that this flexibility ("plasticity") of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization yet requires STAT4 along with T-box expressed in T cells. Surprisingly, loss of either STAT4 or T-box expressed in T cells increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation.

MeSH Terms (18)

Animals Cell Differentiation Cells, Cultured CpG Islands DNA Methylation Immunologic Memory Interferon-gamma Interleukin-4 Lymphocyte Activation Mice Mice, Inbred BALB C Mice, Knockout Mice, Nude Promoter Regions, Genetic STAT4 Transcription Factor T-Box Domain Proteins Th1 Cells Th2 Cells

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