Instability of an epigenetic mark: T-bet and STAT4 influence the symmetry and plasticity of DNA methylation at the IFN-γ promoter in effector and memory Th2 lymphocytes

Abstract

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 cells producing both IFN-γ and IL-4. We now show that this flexibility of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization. We also demonstrate that flexible expression of Ifng requires the transcription factor STAT4, along with T-bet. Surprisingly, loss of either STAT4 or T-bet 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.