A GATA-3 binding site in the first intron of the interleukin-4 gene defines a critical element for the memory expression of interleukin-4 in Th lymphocytes

T lymphocytes can become imprinted for the expression of particular cytokines. This functional memory may be an essential and basic component in the control of rheumatic inflammation. We have shown before that epigenetic modification of cytokine genes is involved in the establishment of a cytokine memory for IL-4.

Here we report identification of a region of the first intron of the interleukin-4 (IL-4) gene that is methylated in naive Th cells and in Th1 cells, but demethylated in IL-4 expressing Th2 cells. This intron sequence (CIS) is conserved in the IL-4 genes of all species analysed so far. The CIS contains two GATA-binding sites. Both binding sites, their orientation and distance are required for specific binding of GATA-3 from Th2 cells. Th cells in which part of the IL-4 gene, including the CIS, is replaced by a gfp-gene, are impaired in their memory for IL-4.

The CIS thus provides a GATA-3 specific nucleus of epigenetic modification of the IL-4 gene, imprinting it for memory expression upon restimulation of the T cell by antigen alone.