Epigenetic Regulation of the Th2 Locus in Fetal and Neonatal T Cells

In naïve adult CD4⁺ T cells, the Th2 locus, containing the Il5, Il13, and Il4 genes, is in a transcriptionally quiescent state. When naïve T cells differentiate into Th2 cells, the Th2 locus undergoes extensive epigenetic modifications which are permissive for gene expression. These modifications, which include the induction of DNase I hypersensitivity, permissive histone modifications, and DNA demethylation at CpG residues, are associated with Th2 differentiation and secretion of Th2 cytokines. Regulatory regions, such as the Il4 and Il13 promoters, the locus control region (LCR), and intra- and intergenic enhancers are the primary targets of these modifications. Unlike adult animals, neonates are considered to be Th2 biased due to the robust development of Th2 lineage cells coupled with a deficiency in Th1 differentiation. This Th2 bias is reflected in the epigenetic status of the Th2 locus. In naïve neonatal CD4⁺ T cells in thymus and lymph nodes, key regulatory regions in the Th2 locus pre-exist in a hypomethylated state and these cells are already primed for Th2 status. Here, we focus on the epigenetic modifications in fetal and neonatal T cells and the association of the Th2 locus hypomethylated status with the characteristics of neonatal Th2 biased immunity.