title: IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA to inhibit MHC II presentation.
abstract: Peptides presentation to T cells by MHC class II molecules is of importance in initiation of immune response to a pathogen. The level of MHC II expression directly influences T lymphocyte activation and is often targeted by various viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) encoded LANA is known to evade MHC class I peptide processing, however, the effect of LANA on MHC class II remains unclear. Here, we report that LANA down-regulates MHC II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA) promoter pIII and pIV in a dose-dependent manner. Strikingly, although LANA knockdown efficiently disrupts the inhibition of CIITA transcripts from its pIII and pIV promoter region, the expression of HLA-DQβ but no other MHC II molecules was significantly restored. Moreover, we revealed that the presentation of HLA-DQβ enhanced by LANA knockdown did not help LANA-specific CD4+ T cell recognition of PEL cells, and the inhibition of CIITA by LANA is independent of IL-4 or IFN-γ signaling but dependent on the direct interaction of LANA with IRF-4 (an activator of both the pIII and pIV CIITA promoters). This interaction dramatically blocked the DNA-binding ability of IRF-4 on both pIII and pIV promoters. Thus, our data implies that LANA can evade MHC II presentation and suppress CIITA transcription to provide a unique strategy of KSHV escape from immune surveillance by cytotoxic T cells.
authors.affiliation: MOE&MOH Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Cai
authors.forename: Shuvomoy
authors.initials: S
authors.lastname: Banerjee
authors.forename: Amanda
authors.initials: A
authors.lastname: Cervini
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hislop
authors.forename: Richard
authors.initials: R
authors.lastname: Dzeng
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D017951:Antigen Presentation; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
chemical_list: D000956:Antigens, Viral; D059866:HLA-DQ beta-Chains; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D015847:Interleukin-4; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099218:Interferon Regulatory Factor-4; C573415:IFNG protein, human; C508598:IL4 protein, human; C083728:MHC class II transactivator protein; C109540:latency-associated nuclear antigen