This grant will investigate the mechanism(s) that coordinately regulate the class II major histocompatibility complex (MHC) genes. The development of an immune response to a pathogen and the avoidance of an immune response to self proteins require the appropriate expression of class II MHC genes. Understanding how these genes are controlled is therefore necessary for understanding how the immune response is regulated. MHC class II genes are coordinately regulated at the level of transcription either developmentally or through the action of cytokines. At the molecular level, a conserved set of cis-acting elements appear to mediate this coordinate regulation; however, we have presented significant evidence that some of the factors that interact with these cis-elements are not the same for all the genes. For example, in the DRA gene, the X- box region element, which is necessary for B-cell specific expression binds two factors, RFX and X2BP; whereas, the homologous sequence of the DRB gene only binds the X2BP factor. How can these genes be coordinately regulated if their homologous cis-acting sequences fail to bind the same factors? One solution to this problem is that although different factors may interact with some of the elements, the signals that are provided by these factors to the general transcription machinery are similar, thereby regulating the genes coordinately. Alternatively, different class II genes may have additional cis-acting sequences that will overcome a deficiency in one or more shared elements. To determine if these hypotheses are correct, this application will compare the regulatory mechanisms of the alpha and beta chain genes that encode the HLA-DR heterodimer. Experiments are designed to: identity the elements important for DRB gene expression; to clone and characterize a newly discovered factor, X2BP, which interacts with both the DRA and DRB genes and may be involved with coordinate regulation of these genes; and to examine the activation signals that class II-specific DNA-binding proteins provide to the transcriptional machinery in both wild-type and class II transcriptional mutant B cells. Preliminary results from our studies suggest a working model for class II gene regulation that involves a co-activator. In this model, the co- activator is defective in one of the class II mutant cell lines thereby preventing class II expression. These ideas will be tested. Results from these studies may lead to the development of novel immune therapies, which will allow the control of antigen presentation and the immune response via the manipulation of class II gene expression.
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