The proposed research will allow mastery of the techniques of molecular biology while also addressing critical questions regarding the initiation and perpetuation of immune-mediated tissue destruction. Aberrant expression of class II major histocompatibility complex antigens occurs in several autoimmune diseases and malignancies, on tissues such as synoviocytes, proximal tubule cells, and melanoma cells. These cells therefore gain the potential to present antigens to T helper lymphocytes and to initiate an inflammatory response. We have been interested in studying the downregulation of class II antigen expression by the cytokine TGFbeta. Our work has identified conserved proximal promoter elements in the HLA-DRalpha gene which mediate this downregulation. We plan to further characterize the molecular mechanism of TGFbeta action by studying the time course and tissue distribution of the effect, as well as the need for phosphorylation, new RNA, and new protein synthesis. We propose to isolate DNA binding proteins and coactivator proteins acting on the class II promoter in response to TGFbeta. In addition, we are developing a mouse model whose gene for mXBP, a transcript ion factor binding the TGFbeta as well as the class II promoters, has been deleted by homologous recombination in ES cells. Our goal is to gain an understanding of the downregulatory mechanism for class II antigens, enabling the design of rational therapies to prevent destructive inflammatory responses.