The long terminal repeat from a thymotropic mouse mammary tumor virus variant, DMBA-LV, was used to drive the expression of two reporter genes, murine c-myc and human CD4, in transgenic mice. Expression was observed specifically in thymic immature cells. Expression of c-myc in these cells induced oligoclonal CD4+CD8+ T-cell thymomas. Expression of human CD4 was restricted to thymic progenitor CD4-CD8-and CD4+CD8+ T cells and was shut off in mature CD4+CD8-and CD4-CD8+ T cells, known to be derived from the progenitor double-positive T cells. These results suggest the existence of similar and common factors in CD4+CD8-and CD4-CD8+ T cells and support a model of differentiation of CD4+CD8+ T cells through common signal(s) involved in turning off the expression of the CD4 or CD8 gene.DMBA-LV leukemia virus is a type B replication-competent thymotropic retrovirus which is highly related to mouse mammary tumor virus (MMTV) (5, 19). However, in contrast to MMTV, known to induce mammary carcinomas (36), DMBA-LV MMTV (MMTVD) induces a high incidence of T-cell leukemias (thymomas) after a short latent period (6). Sequence analysis of the MMTVD long terminal repeat (LTR) revealed that in addition to several point mutations, the U3 region has undergone structural alterations compared with the C3H MMTV LTR (7). These modifications introduce two additional copies of the distal glucocorticoid regulatory element and truncate the 3' end of the open reading frame known to encode a protein exhibiting the characteristics of a superantigen (1, 15). However, the biological significance of these sequence alterations is still unclear. In another class of retroviruses, murine leukemia virus, it has clearly been established that the LTR, and specifically the U3 LTR, harbors the sequences determining the tissue (11, 21, 43) and disease (12,13,20,48) specificity of these viruses.The majority of the DMBA-LV-induced thymomas were found to be of an immature T-cell phenotype, Thy-1.2+, CD4+, CD8+ (Lyt2+), and CD5+ (Lytl+) (37,38 is regulated so that the cells expressing class II-restricted T-cell receptor (TcR) are CD4+CD8-, while those expressing class I-restricted TcR are CD4-CD8+.To determine whether the tissue specificity of DMBA-LV virus was determined by its LTR, and to identify the T-cell subpopulation in which this LTR was most active, we constructed transgenic mouse lines by using the MMTVD LTR as a promoter to drive expression of two independent reporter genes, the murine c-myc proto-oncogene and the human CD4 cDNA. Transgenic mice expressing the MMTVD/c-myc transgene consistently developed clonal or oligoclonal CD4+CD8+ T-cell lymphomas (thymomas). In addition, in mice bearing the MMTVD/CD4 transgene, the human CD4 protein was preferentially expressed in CD4+CD8+ thymic T cells and their progenitors, and its expression was turned off in both CD4+CD8-and CD4-CD8+ mature T cells. These experiments support a model of differentiation of CD4+CD8+ thymic T cells through common signals. MATERMILS AND METHODSConstruction of the transgenes. ...