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.
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.
Heemskerk
Mirjam H M
MH
Department of Hematology, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, The Netherlands. m.h.m.heemskerk@lumc.nl
Hagedoorn
Renate S
RS
van der Hoorn
Menno A W G
MA
van der Veken
Lars T
LT
Hoogeboom
Manja
M
Kester
Michel G D
MG
Willemze
Roel
R
Falkenburg
J H Frederik
JH
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
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