Mature T cells express either CD4 or CD8 on their surface. Most helper T cells 
express CD4, which binds to class II major histocompatibility complex (MHC) 
proteins, and most cytotoxic T cells express CD8, which binds to class I MHC 
proteins. In the thymus, mature CD4+CD8- and CD4-CD8+ T cells expressing alpha 
beta T-cell antigen receptors (TCR) develop from immature thymocytes through 
CD4+CD8+ alpha beta TCR+ intermediates. Experiments using mice transgenic for 
alpha beta TCR suggest that the specificity of the TCR determines the CD4/CD8 
phenotype of mature T cells. These results, however, do not indicate how a T 
cell differentiates into the CD4 or CD8 lineage. Here we show that the CD4 
transmembrane region and/or cytoplasmic tail mediates the delivery of a specific 
signal that directs differentiation of T cells to a CD4 lineage. We generated 
transgenic mice expressing a hybrid molecule composed of the CD8 alpha 
extracellular domains linked to the CD4 transmembrane region and cytoplasmic 
tail. We predicted that this hybrid molecule would bind to class I MHC proteins 
through the extracellular domains but deliver the intracellular signals 
characteristic of CD4. By crossing our transgenic mice with mice expressing a 
transgenic alpha beta TCR specific for a particular antigen plus class I MHC 
protein, we were able to express the hybrid molecule in developing thymocytes 
expressing the class I MHC-restricted TCR. Our results show that the signal 
transduced by the hybrid molecule results in the differentiation of immature 
thymocytes expressing a class I-restricted TCR into mature T cells expressing 
CD4.