title: CD8+ T cell responses against TAP-inhibited cells are readily detected in the human population.
abstract: Target cell recognition by CTLs depends on the presentation of peptides by HLA class I molecules. Tumors and herpes viruses have adopted strategies to greatly hamper this peptide presentation at the important bottleneck, the peptide transporter TAP. Previously, we described the existence of a CD8(+) CTL subpopulation that selectively recognizes such TAP-deficient cells in mouse models. In this study, we show that the human counterpart of this CTL subset is readily detectable in healthy subjects. Autologous PBMC cultures were initiated with dendritic cells rendered TAP-impaired by gene transfer of the viral evasion molecule UL49.5. Strikingly, specific reactivity to B-LCLs expressing one of the other viral TAP-inhibitors (US6, ICP47, or BNLF2a) was already observed after three rounds of stimulation. These short-term T cell cultures and isolated CD8(+) CTL clones derived thereof did not recognize the normal B-LCL, indicating that the cognate peptide-epitopes emerge at the cell surface upon an inhibition in the MHC class I processing pathway. A diverse set of TCRs was used by the clones, and the cellular reactivity was TCR-dependent and HLA class I-restricted, implying the involvement of a broad antigenic peptide repertoire. Our data indicate that the human CD8(+) T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway, and these might be exploited for cancers that are associated with such defects and for infections with immune-evading herpes viruses.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Margit H
authors.initials: MH
authors.lastname: Lampen
authors.forename: Marieke C
authors.initials: MC
authors.lastname: Verweij
authors.forename: Bianca
authors.initials: B
authors.lastname: Querido
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000302:isolation & purification; D018014:Gene Transfer Techniques; D006566:Herpesviridae Infections / Q000276:immunology / Q000473:pathology; D007242:Herpesvirus 1, Bovine / Q000235:genetics / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000235:genetics; D014412:Tumor Virus Infections / Q000276:immunology / Q000473:pathology; D015678:Viral Structural Proteins / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D018984:Epitopes, T-Lymphocyte; D015678:Viral Structural Proteins; C434023:tegument protein VP22, bovine herpesvirus 1; C477327:transporter associated with antigen processing (TAP)