Control of the HLA antigen processing pathways by the HLA class III-encoded BAT3

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The biosynthesis of major histocompatibility gene complex (MHC) encoded class I and class II molecules are peptide receptors, which present antigenic peptides to T lymphocytes. The biosynthesis of MHC class I and class II molecules is critical for antigen presentation. Therefore, regulation of MHC genes is important for the control of immune responses. We discovered that MHC class III encoded BAT3 regulates components of the MHC class I and class II processing pathways. MHC class I and class II genes are regulated on the transcriptional level. Investigation of class II gene regulation revealed that the class II transactivator CIITA is stabilized by expression of BAT3. Both, CIITA and BAT3 genes are induced/enhanced by IFN gammatreatment of cells. Newly synthesized CIITA binds to BAT3. This complex acquires a not yet identified posttranslational modification. In addition, treatment with gamma interferon translocates BAT3 and CIITA from the cytosol to the nucleus, where class II genes are regulated. Recently, we discovered that in addition to class II, class I genes are regulated by BAT3 expression. Differential regulation of MHC classes I and II genes is achieved by alternative BAT3 RNA splicing. The BAT3 gene contains 3 exons which are differentially spliced. Based on the splicing events up to 8 splice variants of BAT3 may exist. We isolated six splice variants of BAT3 from cellular cDNA. One BAT3 variant was identified, which exclusively regulates class II expression, whereas a second variant regulates class I expression. The role of the individual BAT3 variants for MHC class I and/or class II expression will be investigated in this project. The mechanism of MHC class I regulation by BAT3 expression is not yet unravelled. We want to identiy BAT3-regulated factors which impact on class I expression. In addition, we want to explore the mechanism how BAT3 translocates from the cytosol to the nucleus with subsequent regulation of MHC genes. Several cytokines are important for differentiation of antigen presenting cells. Some of these cytokines stimulate BAT3 expression and influence intracellular localization of BAT3. We determined that cytokines which induce differentiation of dendritic cells impact on the BAT3 level and on the composition of BAT3 variants. Stimulation of the BAT3 gene by cytokines will be explored and a possible impact of cytokines on BAT3 RNA splicing will be inspected. Based on the results which we obtained with cell lines, we want to study the role of BAT3 in primary cells. Our aim is to investigate the role of BAT3 and of BAT3 variants for developing dendritic cells and to unravel a novel mechanism for the control of MHC class I and class II expression in antigen presenting cells.