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Abstract
Th1 and Th2 cell fates are traditionally viewed as mutually exclusive, but recent work suggests that these lineages may be more plastic than previously thought. When isolating splenic CD4+ T cells from mice infected with the parasitic helminth Schistosoma mansoni, we observed a defined population of IFN-γ/IL-4 double-positive cells. These IFN-γ+IL-4+ cells showed differences in DNA methylation at the Ifng and Il4 loci when compared with IFN-γ+IL-4− (Th1) and IFN-γ−IL-4+ (Th2) cells, demonstrating that they represent a distinct effector cell population. IFN-γ+IL-4+ cells also displayed a discrete DNA methylation pattern at a CpG island within the body of the Gata3 gene, which encodes the master regulator of Th2 identity. DNA methylation at this region correlated with decreased Gata3 levels, suggesting a possible role in controlling Gata3 expression. These data provide important insight into the molecular mechanisms behind the co-existence of Th1 and Th2 characteristics.
Highlights
Th1 and Th2 cells are specialized subsets of CD4+ T helper cells that respond to different modes of infection and which express the signature cytokines IFN-γ and IL-4, respectively
IFN-γ+IL4+ cells were observed in five separate S. mansoni infections with the proportion varying from approximately 2–9% of CD4+ T cells, demonstrating that IFN-γ+IL-4+ cells can be found in the spleen in a Th2-dominated infection setting
The distinct DNA methylation patterns observed at key immune gene loci in IFN-γ+IL-4+ cells demonstrate that these cells are different on a molecular level from Th1 and Th2 cells and represent a distinct CD4+ T cell population generated during S. mansoni infection
Summary
Th1 and Th2 cells are specialized subsets of CD4+ T helper cells that respond to different modes of infection and which express the signature cytokines IFN-γ and IL-4, respectively. The IFN-γ+IL-4+ cells displayed a distinct DNA methylation signature at key cytokine genes and at Gata3, suggesting that methylation patterns may be important for allowing the stable co-existence of Th1 and Th2 phenotypes. IFN-γ+IL-4+ cells show a distinct DNA methylation pattern at cytokine gene loci and Gata3
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