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Down-Regulation of MHC Class II Expression through Inhibition of CIITA Transcription by Lytic Transactivator Zta during Epstein-Barr Virus Reactivation¹

Dan Li^2,*,, Lu Qian^2,*, Changguo Chen^*,, Ming Shi^*, Ming Yu^*, Meiru Hu^*, Lun Song^*, Beifen Shen^* and Ning Guo^3,*

^* Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People’s Republic of China; Department of Clinical Laboratory, 306th Hospital, Beijing, People’s Republic of China; and Department of Clinical Laboratory, Navy General Hospital, Beijing, People’s Republic of China

The presentation of peptides to T cells by MHC class II molecules is of critical importance in specific recognition to a pathogen by the immune system. The level of MHC class II directly influences T lymphocyte activation. The aim of this study was to identify the possible mechanisms of the down-regulation of MHC class II expression by Zta during EBV lytic cycle. The data in the present study demonstrated that ectopic expression of Zta can strongly inhibit the constitutive expression of MHC class II and CIITA in Raji cells. The negative effect of Zta on the CIITA promoter activity was also observed. Scrutiny of the DNA sequence of CIITA promoter III revealed the presence of two Zta-response element (ZRE) motifs that have complete homology to ZREs in the DR and left-hand side duplicated sequence promoters of EBV. By chromatin immunoprecipitation assays, the binding of Zta to the ZRE₂₂₁ in the CIITA promoter was verified. Site-directed mutagenesis of three conserved nucleotides of the ZRE₂₂₁ substantially disrupted Zta-mediated inhibition of the CIITA promoter activity. Oligonucleotide pull-down assay showed that mutation of the ZRE₂₂₁ dramatically abolished Zta binding. Analysis of the Zta mutant lacking DNA binding domain revealed that the DNA-binding activity of Zta is required for the trans repression of CIITA. The expression of HLA-DR and CIITA was restored by Zta gene silencing. The data indicate that Zta may act as an inhibitor of the MHC class II pathway, suppressing CIITA transcription and thus interfering with the expression of MHC class II molecules.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Natural Science Foundation of China (Grant 30771981), National Basic Research Program of China (973 Program, Grant 2006CB504305), and National High-Tech Research and Development Plan (863 Program, Grant 2006AA02A245).

² D.L. and L.Q. are co-first authors.

³ Address correspondence and reprint requests to Dr. Ning Guo, Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road 27, Beijing 100850, P.R. China. E-mail address: ningguo{at}nic.bmi.ac.cn

⁴ Abbreviations used in this paper: ZRE, Zta-response element; ChIP, chromatin immunoprecipitation; HCMV, human CMV; Ii, invariant chain; NaB, sodium butyrate; pZta, plasmid expressing Flag-tagged Zta; si, small interfering; TPA, 12-O- tetradecanoylphorbol-13-acetate.