Chou Shiuh-Dih, Khan A Nazmul H, Magner William J, Tomasi Thomas B
Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
Int Immunol. 2005 Nov;17(11):1483-94. doi: 10.1093/intimm/dxh326. Epub 2005 Oct 6.
The regulation of MHC class II expression by the class II transactivator (CIITA) is complex and differs in various cell types depending on the relative activity of three CIITA promoters. Here we show that, in plasma cell tumors, the deacetylase inhibitor trichostatin A (TSA) elicits PIII-CIITA but does not activate the IFN-gamma-inducible PIV-CIITA promoter. In trophoblast cells, all CIITA promoter types are constitutively silent and not induced by IFN-gamma or TSA treatment. TSA induction of PI-CIITA was restricted to macrophage and dendritic cell lines. In the Colon 26 tumor IFN-gamma induced endogenous PIV-CIITA but not PIII-CIITA while TSA activated class II in the apparent absence of CIITA. Reporter assays in Colon 26 showed that TSA induced PIII-CIITA but not PIV-CIITA. Transfection of a dominant negative CIITA plasmid in Colon 26 inhibited induction of class II by IFN-gamma but not TSA. Thus, the potential for both CIITA-dependent and -independent pathways of MHC induction exists within a single cell. Further evidence of CIITA-independent class II expression elicited by TSA was obtained using knockout mice with defects in CIITA, STAT-1alpha and IRF-1 expression. TSA treatment can also activate class II expression in mutant cell lines with deficiencies in signaling molecules, transcription factors and the BRG-1 cofactor that are required for IFN-gamma-induced CIITA expression. Importantly, after epigenetic activation by the deacetylase inhibitor, MHC class II is transported and displayed on the cell surface of a plasma cell tumor and it is converted to an efficient antigen presenting cell for protein and class II-peptide presentation.
II类反式激活因子（CIITA）对MHC II类分子表达的调控十分复杂，在不同细胞类型中存在差异，这取决于三个CIITA启动子的相对活性。我们在此表明，在浆细胞瘤中，去乙酰化酶抑制剂曲古抑菌素A（TSA）可诱导III型CIITA，但不会激活IFN-γ诱导的IV型CIITA启动子。在滋养层细胞中，所有CIITA启动子类型均处于组成性沉默状态，且不会被IFN-γ或TSA处理诱导。TSA对I型CIITA的诱导作用仅限于巨噬细胞和树突状细胞系。在结肠26肿瘤中，IFN-γ可诱导内源性IV型CIITA而非III型CIITA，而TSA在明显不存在CIITA的情况下激活II类分子。结肠26中的报告基因检测表明，TSA可诱导III型CIITA而非IV型CIITA。在结肠26中转入显性负性CIITA质粒可抑制IFN-γ对II类分子的诱导，但不影响TSA的诱导作用。因此，在单个细胞内存在依赖CIITA和不依赖CIITA的MHC诱导途径。利用在CIITA、STAT-1α和IRF-1表达方面存在缺陷的基因敲除小鼠，获得了TSA引发不依赖CIITA的II类分子表达的进一步证据。TSA处理还可激活在信号分子、转录因子以及IFN-γ诱导的CIITA表达所需的BRG-1辅因子方面存在缺陷的突变细胞系中的II类分子表达。重要的是，在经去乙酰化酶抑制剂进行表观遗传激活后，MHC II类分子会被转运并呈现在浆细胞瘤的细胞表面，并且它会转变为一种高效的抗原呈递细胞，用于蛋白质和II类肽的呈递。
