title: Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex.
abstract: Genetic engineering of T lymphocytes is an attractive strategy to specifically redirect T-cell immunity toward viral infections and malignancies. We previously demonstrated redirected antileukemic reactivity of cytomegalovirus (CMV)-specific T cells by transfer of minor histocompatibility antigen HA-2-specific T-cell receptors (TCRs). HA-2-TCR-transferred CMV-specific T cells were potent effectors against HA-2-expressing leukemic cells, as well as CMV-expressing cells. Functional activity of these T cells correlated with TCR cell-surface expression. In the present study we analyzed which properties of transferred and endogenous TCRs are crucial for efficient cell-surface expression. We demonstrate that expression of the introduced TCR is not a random process but is determined by characteristics of both the introduced and the endogenously expressed TCR. The efficiency of TCR cell-surface expression is controlled by the intrinsic quality of the TCR complex. In addition, we demonstrate that chimeric TCRs can be formed and that efficiency of TCR expression is independent of whether TCRs are retrovirally introduced or naturally expressed. In conclusion, introduced, endogenous, and chimeric TCRs compete for cell-surface expression in favor of the TCR-CD3 complex with best-pairing properties.
authors.affiliation: Department of Hematology, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, The Netherlands. m.h.m.heemskerk@lumc.nl
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.forename: Renate S
authors.initials: RS
authors.lastname: Hagedoorn
authors.forename: Menno A W G
authors.initials: MA
authors.lastname: van der Hoorn
authors.forename: Lars T
authors.initials: LT
authors.lastname: van der Veken
authors.forename: Manja
authors.initials: M
authors.lastname: Hoogeboom
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002478:Cells, Cultured / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D017930:Genes, Reporter; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D005822:Genetic Vectors / Q000235:genetics; D015789:HLA-A2 Antigen / Q000276:immunology*; D015793:HLA-B7 Antigen / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D037182:T-Cell Antigen Receptor Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D015789:HLA-A2 Antigen; D015793:HLA-B7 Antigen; D006683:HLA-DQ Antigens; C410042:HLA-DQ5 antigen; D007135:Immunoglobulin Variable Region; D008024:Ligands; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011993:Recombinant Fusion Proteins