Molecular mechanisms of differentiation of a naive CD4⁺ T cell into Th2 cells. A naive CD4⁺ T cell contains a condensed chromatin structure with extensive methylation. Antigen stimulation and engagement of the IL-4R result in STAT6 activation, which, in turn, causes specific demethylation around the IL-4/IL-5/IL-13 locus (similarly, antigen + IL-12 causes demethylation around the IFN-γ locus). Chromatin remodeling is accompanied by induction of Th2-specific transcription factors such as GATA-3 and c-Maf, which bind to target sequences in the IL-4/IL-5/IL-13 locus. The chromatin — rendered accessible by demethylation and perhaps by binding of GATA-3, c-Maf, and other, currently undiscovered Th2-specific transcription factors — is next bound by more widely expressed and transiently induced transcription factors such as AP-1, NF-κB, NF-ATc, and C/EBPβ. This may allow synergistic interactions between the tissue-specific and general transcription factors to occur, resulting in the active transcription of the IL-4, IL-5, and IL-13 genes. Effector/memory cells are thought to be in a state of suspended animation, with an open chromatin structure and high levels of GATA-3 and c-Maf expression. Restimulation of these cells by antigen would result in transient induction of the general factors leading to rapid induction of Th2 gene expression.