Class II MHC genes (for example, the human HLA-DRA gene) are expressed at the cell surface in many professional and nonprofessional antigen-presenting cells in a variety of anatomical locations. Here, we report about 13 mouse transgenic lines (11 of which have not been previously described) generated with four distinct sets of DRA transgenes carrying progressive, informative 5' and 3' deletions. DRA expression was assessed in B lymphocytes, dendritic cells, macrophages, and extra-hematopoietic cells (particularly kidney epithelial cells). A compact transcriptional unit was identified that efficiently directs DRA expression [both constitutive and interferon (IFN)-gamma induced] in extra-hematopoietic tissues and dendritic cells. It extends from position -266 upstream of the transcription initiation site to position +119 downstream of the last DRA exon. The same fragment, however, did not efficiently direct IFN-gamma-induced DRA expression in macrophages, that required additional 5' sequences. Thus, IFN-gamma uses distinct promoter segments and mechanisms to up-regulate class II in different cell lineages. In contrast to previous results in transgenic mice expressing murine class II transgenes, we were unable to generate reproducible patterns of HLA-DRA expression in B cells.