title: Suppression of antigen-specific T cell responses by the Kaposi's sarcoma-associated herpesvirus viral OX2 protein and its cellular orthologue, CD200.
abstract: Regulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein. In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-γ) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200.
authors.affiliation: School of Cancer Sciences, CR UK Centre for Cancer Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Misstear
authors.forename: Simon A
authors.initials: SA
authors.lastname: Chanas
authors.forename: S A Rahim
authors.initials: SA
authors.lastname: Rezaee
authors.forename: Rachel
authors.initials: R
authors.lastname: Colman
authors.forename: Laura L
authors.initials: LL
authors.lastname: Quinn
authors.forename: Heather M
authors.initials: HM
authors.lastname: Long
authors.forename: Oliver
authors.initials: O
authors.lastname: Goodyear
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hislop
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled / Q000276:immunology / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*; D037521:Virulence Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D052118:Lysosomal-Associated Membrane Protein 1; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014764:Viral Proteins; D037521:Virulence Factors; D007371:Interferon-gamma; C042739:antigens, CD200