Th1/Th2 cell differentiation and chromatin remodeling of the Th2 cytokine gene locus

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Differentiation of naive CD4 T cells into Th2 cells is accompanied by chromatin remodeling including hyperacetylation of histones H3 and H4 in the nucleosomes associated with the IL-4,IL-13 and IL-5 genes. A conserved GATA3 response element (CGRE) containing four GATA consensus sequences was identified 1.6 kbp upstream of the IL-13 gene, corresponding with the 5' border of the Th2-specific histone hyperacetylation region. The CGRE was shown to bind to GATA3, histone acetyl transferase complexes including CBP/p300, and RNA polymerase II. Thus, the CGRE may play a crucial role for GATA3-mediated targeting and downstream spreading of core histone hyperacetylation within the IL-13 and IL-4 gene loci. As for the IL-5 gene locus, CD28-costimulation selectively enhanced histone hyperacetylation through NF-kB activation and subsequent upregulation of GATA3. Chromatin remodeling of type 2 cytokine gene loci occurs also in developing CD8 Tc2 T cells. IL-4 production and histone hyperacetylation in IL-4-associated nucleosomes in developing Tc2 cells were significantly lower than those of Th2 cells, however, cytokine production and histone hyperacetylation of IL-5 and IL-13 genes were equivalent. Developing Tc2 cells expressed lower GATA3 levels and dramatically increased levels of repressor of GATA (ROG). A ROG response element in the IL-13 gene exon 4 displayed Tc2-specific bin4ing of ROG,HDAC1 and HDAC2, and exhibited repression of IL-4 gene activation. Thus, ROG may confer CD8 T cell-specific repression of histone hyperacetylation and activation of the IL-4 gene locus.