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 resulted 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, consisting of at least three enhancers, one promoter and one silencer. Here we present evidence that CD4 gene expression is negatively regulated by ZEB. We show that ZEB binds to the 5'E-box in the CD4-3 element of the proximal CD4 enhancer in competition with the transcriptional activators E12 and HEB, thereby reducing CD4 expression on CD4 single-positive but not CD4/CD8 double-positive T cells. The conversion of the CD4 proximal enhancer into a potential silencer element by the transcriptional repressor ZEB offers an additional concept of CD4 gene regulation in T cells.