Positive selection induces CD4 promoter and enhancer function.

Developmental expression of the CD4 gene in mature T cells is controlled by at least four transcriptional control elements: a promoter, two enhancers and a silencer. In this report we use a transgenic approach to study the mechanisms in which these elements interact to convey appropriate tissue- and cell-specific expression at all stages of T cell development. Our data indicate that the control of CD4 gene expression requires the interaction of multiple elements functioning in different combinations at different stages of T cell development. Expression of the CD4 gene in immature CD4+CD8+ thymocytes requires a third enhancer element located in the 3' flanking region of the CD4 gene. Interestingly, the CD4 promoter and proximal/distal enhancers first begin to function at the HSAlo CD69lo H-2Khi CD4 single-positive stage; cells of this phenotype are believed to have survived positive selection. These data indicate that the CD4 promoter and late enhancer elements are induced by positive selection; thus, the final maturation process is an active event that requires the initiation of a novel program of gene expression.