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

幼稚CD 4 T细胞分化为Th 2细胞伴随着染色质重塑，包括与IL-4、IL-13和IL-5基因相关的核小体中组蛋白H3和H4的超乙酰化。在IL-13基因上游1.6kbp处发现了一个保守的GATA 3应答元件（CGRE），该元件含有4个加塔共有序列，对应于Th 2特异性组蛋白高乙酰化区的5'端边界。CGRE显示与GATA 3、组蛋白乙酰转移酶复合物（包括CBP/p300）和RNA聚合酶II结合。因此，CGRE可能在IL-13和IL-4基因座内的核心组蛋白超乙酰化的GATA 3介导的靶向和下游扩散中发挥关键作用。至于IL-5基因位点，CD 28共刺激通过NF-κ B激活和随后的GATA 3上调选择性地增强组蛋白超乙酰化。2型细胞因子基因位点的染色质重塑也发生在发育中的CD 8 Tc 2 T细胞中。在发育中的Tc 2细胞中IL-4产生和IL-4相关核小体中的组蛋白超乙酰化显著低于Th 2细胞，然而，IL-5和IL-13基因的细胞因子产生和组蛋白超乙酰化是相当的。发育中的Tc 2细胞表达较低的GATA 3水平和显著增加的加塔阻遏物（ROG）水平。IL-13基因外显子4中的ROG反应元件显示出ROG、HDAC 1和HDAC 2的Tc 2特异性结合，并显示出对IL-4基因活化的抑制。因此，ROG可以赋予CD 8 T细胞特异性抑制组蛋白超乙酰化和激活IL-4基因座。

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.