The expression of the CD4 gene undergoes a complex pattern of regulation during T cell development. Results obtained in transgenic mice suggest that a combination of proximal enhancer and a silencer from the CD4 gene is sufficient to obtain a developmentally controlled expression along T cell maturation. We generated transgenic mice expressing the human CD4 cDNA under the control of the human CD4 promoter and the murine CD4 minimal proximal enhancer. No other regulatory sequences, including the silencer, were included. The pattern of expression of this transgene is restricted to mature peripheral T cells, to the only mature heat-stable Ag(HSA)low/- single positive thymocytes, and to some NK cells. Surprisingly, no expression was found in double positive or in immature HSAhigh single positive thymocytes. These results suggest that additional, yet uncharacterized genomic sequences are necessary for CD4 expression in immature thymocytes and that there is a change in transcription factors occurring at the late states of T cell development. Finally, since this is the first combination of regulatory sequences that possess such a T mature specific pattern of expression, it should provide a novel tool to address several immunologic questions or for therapeutic purposes.