Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process. Specifically, the inhibition was found to be STAT6 dependent, and HDAC9 was involved with the process of histone deacetylation at the Foxp3 locus, subsequently decreasing chromatin accessibility and Foxp3 gene transcription. Pan-histone deacetylation inhibitors, especially sodium butyrate, notably abolished the inhibitory effects of IL-4 and ameliorated allergic airway inflammation in mouse models.
Fig: IL-4 inhibits Foxp3 transcription and histone acetylation of Foxp3 locus: Naive CD4+ T cells from WT mice were cultured under Treg-polarizing conditions with or without IL-4. A Cells were harvested 3 days later and analyzed by FCM. The percentages of Foxp3+ cells are displayed in the quadrants. B On day 2, cells were harvested and analyzed by quantitative RT-PCR. The graphs display the relative mRNA expression of Foxp3, Gata3, Il9, and Il4. C On day 2, cells were prepared for ATAC-seq. Integrative Genomics Viewer (IGV) screenshots of representative ATAC-seq tracks from each group at the Foxp3 locus are shown. Red bands represent classic regulatory regions. The scales of the two tracks were adjusted to display comparable intensities, and the data are representative of two biologically independent pooled samples. D, EChIP-qPCR analyses for H3Ac, H4Ac, H3K27Ac, H3K9Ac, H3K9Me2, H3K9Me3, H3K27Me2, and H3K27Me3 alterations at the Foxp3 locus were performed. Data are the mean ± SD and representative of three independent experiments. *p < 0.05.
Our research provides important mechanistic insights into how IL-4 inhibits regulatory T cells differentiation and suggests the therapeutic potential of the sodium butyrate in allergic airway disease.
Cui, J., Xu, H., Yu, J. et al. IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation. Cell Death Dis 12, 501 (2021). https://doi.org/10.1038/s41419-021-03769-7