title: Kaposi's sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3.
abstract: Endothelial cells (EC) can present antigen to either CD8(+) T lymphocytes through constitutively expressed major histocompatibility complex class I (MHC-I) or CD4(+) T lymphocytes through gamma interferon (IFN-γ)-induced MHC-II. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), an EC neoplasm characterized by dysregulated angiogenesis and a substantial inflammatory infiltrate. KSHV is understood to have evolved strategies to inhibit MHC-I expression on EC and MHC-II expression on primary effusion lymphoma cells, but its effects on EC MHC-II expression are unknown. Here, we report that the KSHV infection of human primary EC inhibits IFN-γ-induced expression of the MHC-II molecule HLA-DR at the transcriptional level. The effect is functionally significant, since recognition by an HLA-DR-restricted CD4(+) T-cell clone in response to cognate antigen presented by KSHV-infected EC was attenuated. Inhibition of HLA-DR expression was also achieved by exposing EC to supernatant from KSHV-inoculated EC before IFN-γ treatment, revealing a role for soluble mediators. IFN-γ-induced phosphorylation of STAT-1 and transcription of CIITA were suppressed in KSHV-inoculated EC via a mechanism involving SOCS3 (suppressor of cytokine signaling 3). Thus, KSHV infection resulted in transcriptional upregulation of SOCS3, and treatment with RNA interference against SOCS3 relieved virus-induced inhibition of IFN-γ-induced STAT-1 phosphorylation. Since cell surface MHC-II molecules present peptide antigens to CD4(+) T lymphocytes that can function either as direct cytolytic effectors or to initiate and regulate adaptive immune responses, inhibition of this antigen-presenting pathway would provide a survival advantage to the virus.
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: L M
authors.initials: LM
authors.lastname: Butler
authors.forename: H C
authors.initials: HC
authors.lastname: Jeffery
authors.forename: R L
authors.initials: RL
authors.lastname: Wheat
authors.forename: H M
authors.initials: HM
authors.lastname: Long
authors.forename: P C
authors.initials: PC
authors.lastname: Rae
authors.forename: G B
authors.initials: GB
authors.lastname: Nash
authors.forename: D J
authors.initials: DJ
authors.lastname: Blackbourn
mesh_terms: D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology* / Q000821:virology; D006684:HLA-DR Antigens / Q000096:biosynthesis*; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014158:Transcription, Genetic
chemical_list: D006684:HLA-DR Antigens; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators