title: The varicellovirus-encoded TAP inhibitor UL49.5 regulates the presentation of CTL epitopes by Qa-1b1.
abstract: Impairment of MHC class I Ag processing is a commonly observed mechanism that allows viruses and tumors to escape immune destruction by CTL. The peptide transporter TAP that is responsible for the delivery of MHC class I-binding peptides into the endoplasmic reticulum is a pivotal target of viral-immune evasion molecules, and expression of this transporter is frequently lost in advanced cancers. We recently described a novel population of CTL that intriguingly exhibits reactivity against such tumor-immune escape variants and that recognizes self-peptides emerging at the cell surface due to defects in the processing machinery. Investigations of this new type of CTL epitopes are hampered by the lack of an efficient inhibitor for peptide transport in mouse cells. In this article, we demonstrate that the varicellovirus protein UL49.5, in contrast to ICP47 and US6, strongly impairs the activity of the mouse transporter and mediates degradation of mouse TAP1 and TAP2. Inhibition of TAP was witnessed by a strong reduction of surface MHC class I display and a decrease in recognition of conventional tumor-specific CTL. Analysis of CTL reactivity through the nonclassical molecule Qa-1(b) revealed that the presentation of the predominant leader peptide was inhibited. Interestingly, expression of UL49.5 in processing competent tumor cells induced the presentation of the new category of peptides. Our data show that the varicellovirus UL49.5 protein is a universal TAP inhibitor that can be exploited for preclinical studies on CTL-based immune intervention.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands. T.van_Hall@lumc.nl
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.forename: Danijela
authors.initials: D
authors.lastname: Koppers-Lalic
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
authors.forename: Calin
authors.initials: C
authors.lastname: Precup
authors.forename: Patrick
authors.initials: P
authors.lastname: Asmawidjaja
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002460:Cell Line; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000145:classification / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D018140:Varicellovirus / Q000276:immunology*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D010455:Peptides; C032907:Q surface antigens; D014764:Viral Proteins; D007371:Interferon-gamma