International Immunology Advance Access originally published online on October 6, 2005
International Immunology 2005 17(11):1483-1494; doi:10.1093/intimm/dxh326
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Histone acetylation regulates the cell type specific CIITA promoters, MHC class II expression and antigen presentation in tumor cells
1 Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA
2 Departments of Medicine and Microbiology and Immunology, State University of New York, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA
Correspondence to: T. B. Tomasi; E-mail: thomas.tomasi{at}roswellpark.org
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-
-inducible PIV-CIITA promoter. In trophoblast cells, all CIITA promoter types are constitutively silent and not induced by IFN- or TSA treatment. TSA induction of PI-CIITA was restricted to macrophage and dendritic cell lines. In the Colon 26 tumor IFN- 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- 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-1
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--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.
Keywords: gene regulation, promoter-specific CIITA
Transmitting editor: L. Glimcher
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