title: TAP-inhibiting proteins US6, ICP47 and UL49.5 differentially affect minor and major histocompatibility antigen-specific recognition by cytotoxic T lymphocytes.
abstract: CTLs specific for hematopoietic system-restricted minor histocompatibility antigens (mHags) can serve as reagents for cellular adoptive immunotherapy after allogeneic stem cell transplantation (SCT). In the HLA-mismatched setting, CTLs specific for hematopoietic system-restricted mHags expressed solely by the non-self 'allo' HLA molecules could be used to treat relapse after HLA-mismatched SCT. The generation of mHag-specific allo-HLA-restricted CTLs requires antigen-presenting cells (APCs) expressing low numbers of endogenous peptides to avoid co-induction of undesired allo-HLA reactivities. In this study, we exploited viral evasion strategies to generate APCs expressing a controlled set of endogenous peptides. Herpesviruses persist lifelong following primary infection due to expression of viral gene products that hamper T-cell recognition of infected cells. The herpesvirus-derived proteins US6, ICP47 and UL49.5 down-regulate endogenous antigen presentation in human APCs via inhibition of the transporter associated with antigen processing. EBV-transformed B cell lines transduced with retroviral vectors encoding US6, ICP47 or UL49.5 exhibited a stable decrease in cell-surface HLA class I expression and were protected from lysis by mHag-specific CTLs. Exogenous addition of mHag peptide fully restored target cell recognition. UL49.5 showed the most pronounced inhibitory effect, reducing HLA class I expression and mHag-specific lysis up to 99%. UL49.5 also significantly diminished allo-HLA reactivities mediated by allo-HLA-specific CTLs. In conclusion, UL49.5 could be a powerful new tool to study and modulate endogenous antigen presentation.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2300RC, Leiden, The Netherlands. l.e.m.oosten.@lumc.nl
authors.forename: Liesbeth E M
authors.initials: LE
authors.lastname: Oosten
authors.forename: Danijela
authors.initials: D
authors.lastname: Koppers-Lalic
authors.forename: Els
authors.initials: E
authors.lastname: Blokland
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D017951:Antigen Presentation / Q000276:immunology*; D002460:Cell Line; D006649:Histocompatibility Antigens / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000276:immunology*; D008024:Ligands; D010455:Peptides / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D006649:Histocompatibility Antigens; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D008024:Ligands; D010455:Peptides; D016601:RNA-Binding Proteins; C073119:TAP1 protein, human; C099455:UL49.5 protein, bovine herpesvirus type 1; C432877:US6 protein, Human cytomegalovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins