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Kaposi's sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3.

Butler, LM, Jeffery, HC, Wheat, RL, Long, HM, Rae, PC, Nash, GB and Blackbourn, DJ (2012) Kaposi's sarcoma-associated herpesvirus inhibits expression and function of endothelial cell major histocompatibility complex class II via suppressor of cytokine signaling 3. J Virol, 86 (13). pp. 7158-7166.

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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.

Item Type: Article
Authors :
NameEmailORCID
Butler, LMUNSPECIFIEDUNSPECIFIED
Jeffery, HCUNSPECIFIEDUNSPECIFIED
Wheat, RLUNSPECIFIEDUNSPECIFIED
Long, HMUNSPECIFIEDUNSPECIFIED
Rae, PCUNSPECIFIEDUNSPECIFIED
Nash, GBUNSPECIFIEDUNSPECIFIED
Blackbourn, DJd.blackbourn@surrey.ac.ukUNSPECIFIED
Date : July 2012
Identification Number : https://doi.org/10.1128/JVI.06908-11
Uncontrolled Keywords : Cells, Cultured, Down-Regulation, Endothelial Cells, HLA-DR Antigens, Herpesvirus 8, Human, Host-Pathogen Interactions, Humans, Immune Tolerance, Nuclear Proteins, Suppressor of Cytokine Signaling Proteins, Trans-Activators, Transcription, Genetic
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:51
Last Modified : 17 May 2017 14:45
URI: http://epubs.surrey.ac.uk/id/eprint/825378

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