IRF-4-Mediated CIITA Transcription Is Blocked by KSHV Encoded LANA to Inhibit MHC II Presentation

PLoS Pathogens

Erle S. Robertson¹  Shuvomoy Banerjee¹  Amanda Cervini¹  Richard Dzeng¹  Jie Lu¹  Qiliang Cai²  Andrew D. Hislop³ 

[1] Department of Microbiology and the Tumor Virology Program of Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America;MOE&MOH Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China;School of Cancer Sciences and Medical Research Council Centre for Immune Regulation, The University of Birmingham, Birmingham, United Kingdom

关键词: Major histocompatibility complex;    T cells;    Transcription factors;    Immunoprecipitation;    B cells;    Gene expression;    DNA-binding proteins;    Immunoblotting;   

DOI  :  10.1371/journal.ppat.1003751

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY