Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB

ZEB, an E-box binding transcriptional repressor, is an important regulator of T cell and muscle development. Targeted disruption of ZEB in mice result ed in a strong reduction of thymocytes and the few T cells that reached the mature stage were predominantly CD4(+). CD4 expression during the various stages of T cell differentiation is controlled at the transcriptional level by a complex array of regulatory elements in the CD4 gene locus, consistin g of at least three enhancers, one promoter and one silencer. Here we prese nt evidence that CD4 gene expression is negatively regulated by ZEB. We sho w that ZEB binds to the 5'E-box in the CD4-3 element of the proximal CD4 en hancer in competition with the transcriptional activators E12 and HEB, ther eby reducing CD4 expression on CD4 single-positive but not CD4/CD8 double-p ositive T cells. The conversion of the CD4 proximal enhancer into a potenti al silencer element by the transcriptional repressor ZEB offers an addition al concept of CD4 gene regulation in T cells.