Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)

The specific cytokine secreted by dendritic cells to initiate Th2 differentiation is not conclusively known but may be Interleukin-2 (IL2) (Granucci et al. 2001, 2003). IL2 from either dendritic cells or T cells activates signaling in the T cell that yields phosphorylated STAT5 dimers. The STAT5 dimers bind and activate the gene encoding IL4R, a receptor subunit for IL4, and cause opening of chromatin at the IL4 locus. IL4 signaling in the CD4+ T cell produces phosphorylated STAT6 dimers that bind the gene encoding GATA3 (Onodera et al. 2010, reviewed in Onodera et al. 2018), the master regulator of Th2 differentiation.The STAT6 dimers also bind a locus control region (LCR) in the 3' region of the RAD50 gene, which is located in a gene cluster that contains genes encoding the Th2 cytokines IL4, IL5, and IL13, and promote their expression. Expression of GATA3 is also activated by NFATC2 (NFAT1), from TCR signaling (Scheiman and Avri et al. 2009), and NICD1 and NICD2, from Notch signaling (Amsen et al. 2004, 2007, Fang et al. 2007, reviewed in Nakayama and Yamashita 2008, Zhu et al. 2010).

GATA3 is sufficient to direct Th2 differentiation, including expression of Th2-characteristic cytokines. GATA3, STAT6 dimers, and other factors bind the LCR and recruit chromatin modifiers to open chromatin in the region by acetylating histones.

Th2 cells are characterized by the expression and secretion of the cytokines IL4, IL5, and IL13, which are encoded by genes located with the LCR in a cluster on human chromosome 5 (chromosome 11 in mice). GATA3, NFATC2 and other factors bind the promoters of the IL4 gene and IL13 gene and activate expression. GATA3 binds the IL5 gene and can activate or repress it expression, depending on the binding site.