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

编码I类和II类分子的主要组织相容性基因复合体(MHC)的生物合成是多肽受体，将抗原肽呈递给T淋巴细胞。MHC I类和II类分子的生物合成是抗原提呈的关键。因此，MHC基因的调控对免疫应答的控制具有重要意义。我们发现，MHC III类编码的BAT3调控MHC I类和II类处理途径的组成部分。MHC I类和II类基因在转录水平上受到调控。对第二类基因调控的研究表明，第二类反式激活因子CIITA是通过BAT3的表达稳定的。CIITA和BAT3基因都是由细胞干扰素诱导/增强的。新合成的CIITA与BAT3结合。这个复合体获得了一种尚未确定的翻译后修饰。此外，伽玛干扰素治疗会将BAT3和CIITA从胞浆转移到细胞核，在那里II类基因受到调控。最近，我们发现除了第II类基因外，第I类基因还受BAT3的表达调控。MHC I和II类基因的差异调控是通过替代BAT3 RNA剪接实现的。BAT3基因包含3个差异剪接的外显子。根据剪接事件，BAT3可能存在多达8个剪接变体。我们从细胞中分离到了6个BAT3的剪接变异体。确定了一个BAT3变异体，它只调节II类基因的表达，而第二个变异体调控I类基因的表达。在这个项目中，将研究MHC I类和/或II类表达的单个BAT3变体的作用。BAT3基因表达对MHC-I类分子的调控机制尚不清楚。我们希望找出影响I类基因表达的BAT3调节因子。此外，我们还想探讨BAT3如何从胞浆移位到细胞核，进而调控MHC基因。几种细胞因子对抗原提呈细胞的分化很重要。其中一些细胞因子刺激BAT3的表达并影响BAT3在细胞内的定位。我们确定了诱导树突状细胞分化的细胞因子影响BAT3水平和BAT3变体的组成。将探索细胞因子对BAT3基因的刺激，并检查细胞因子对BAT3 RNA剪接的可能影响。基于我们在细胞系上获得的结果，我们想要研究BAT3在原代细胞中的作用。我们的目的是研究BAT3和BAT3变异体在树突状细胞发育中的作用，并揭示一种新的机制来控制抗原提呈细胞中MHC I和II类的表达。

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.