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

Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells) Naive (unexposed to antigen) CD4+ T cells are induced to differentiate into T helper 2 cells (Th2 cells) by encounters with dendritic cells presenting antigen peptides on MHC II complexes (reviewed in León 2023). Antigen peptides activate signaling by the T cell receptor (TCR) which is amplified by the interaction between CD80 or CD86 on the dendritic cell and CD28 on the T cell (reviewed in León 2023). Dendritic cells also secrete cytokines that determine the differentiation of CD4+ T cells into various helper and regulatory subtypes, a process called polarization.
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 (Liao et al. 2008), a receptor subunit for IL4, and cause opening of chromatin at the IL4 locus (Cote-Sierra et al. 2004). 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 (Lee and Rao 2004), which is located in a gene cluster that contains genes encoding the Th2 cytokines IL4, IL5, and IL13, and promote their expression (Lee et al. 2003). 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 (Ouyang et al. 2000). GATA3 (Kanhere et al. 2012), STAT6 dimers (Lee and Rao 2004), and other factors bind the LCR and recruit chromatin modifiers to open chromatin in the region by acetylating histones (Wurster and Pazin 2008).
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 (Zheng and Flavell 1997, Sasaki et al. 2013, Hosokawa et al. 2013, Szabo et al. 1993, Rooney et al. 1995, Takemoto et al. 1997) and IL13 gene (Kishikawa et al. 2001, Yamashita et al. 2002, Yao et al. 2012, Hosokawa et al. 2013, Sasaki et al. 2013) and activate expression. GATA3 binds the IL5 gene and can activate or repress it expression, depending on the binding site (Schwenger et al. 2001, Zhang et al. 1997, Lee et al. 1998, Sasaki et al. 2013).