Cell surface antigens encoded by the major histocompatibility gene complex (MHC) function in the associative recognition of foreign antigens by T lymphocytes, and the levels of their expression affect both the induction and effector phases of immune responses. The expression of MHC antigens can be modulated by several soluble mediators, perhaps the most significant being the interferons (IFNs) which can be viewed as being potent immunopotentiators. Variability has been observed in the MHC-inducing activities depending on the type of interferon, the MHC gene, and the cell type. Type I interferons (alpha and beta, produced by virus-infected cells) stimulate increases in the levels of class I MHC antigens in most cell types but have no effect on class II antigen expression. Type II interferon (gamma, produced by activated T cells) stimulate increases in class I expression and induce the expression of class II antigens on some cell types, including macrophages and several epithelial and endothelial cells. The long range goal of this research is to understand the physiological regulation of expression of MHC antigens, both in normal individuals and in instances where aberrant MHC antigen expression may be associated with immunopathological conditions (such as graft rejection and autoimmunity). During this grant period our efforts will focus on elucidating the molecular mechanisms by which the interferons stimulate increased class I expression and induce class II expression on various murine tissues. Our previous studies on the effects of IFN-gamma on the WEHI-3 macrophage cell line suggest differences in the contribution of transcriptional and post-transcriptional effects on IFN-gamma on expression of class I and class II antigens and their associated chains, beta2- microglobulin and the invariant chain. We will quantitate the contributions of increased transcription rates and mRNA stabilization to the increased levels of MHC mRNAs in WEHI-3 cells and normal peritoneal macrophages. These analyses will be extended to the type I interferons and to other cell types (using primary cell cultures) to assess interferon- and tissue-specific variations in the mechanisms of stimulation of MHC expression. Responsiveness of the various class I genes will be assessed by using a set of gene-specific synthetic oligonucleotide probes, and responses of individual class I and class II genes will be monitored in mice of different H-2 haplotypes to investigate the possibility that allele-specific differences in regulation of the levels of MHC antigens could influence immune responsiveness and disease susceptibility. We will determine the mechanisms of action of agents that modulate interferon responses: prostaglandins and glucocorticoids, which inhibit IFN-gamma-induced class II expression, and tumor necrosis factor and lymphotoxin, which synergize with IFN-gamma to increase the level of class II induction. Finally, we will investigate the mechanisms of transcriptional regulation of MHC expression, using in vitro transcription assays and assays that detect binding of nuclear proteins to DNA, to identify cis-acting regulatory elements and trans-acting factors. It is hoped that these studies will facilitate development or approaches to modulate aberrant MHC antigen expression associated with various pathological conditions.
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