A unique DNA methylation signature defines a population of IFN-γ/IL-4 double-positive T cells during helminth infection

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. © 2014 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.