title: Unpredicted phenotypes of two mutants of the TcR DMF5.
abstract: When a T-cell Receptor (TcR) interacts with its cognate peptide-MHC (pMHC), it triggers activation of a signaling cascade that results in the elicitation of a T cell effector function. Different models have been proposed to understand which parameters are needed to obtain an optimal activation of the signaling. It was speculated that improving the binding of a TcR could bring a stronger pMHC recognition, hence a stronger stimulation of the T cell. However, it was recently shown that an increase in affinity does not seem to be sufficient to guarantee improved functionality. A combination of factors is necessary to place the modified TcR in an optimal functional window. We here compared the binding parameters of two mutants of the melanoma antigen peptide MART-127-35 specific TcR DMF5. The first mutant was previously isolated by others in a screen for improved TcR. It was reported to have an increased CD8-independent activity. We confirmed these data and showed that the enhancement was neither due to change in half life (t1/2) nor Kd of the pMHC-TcR complex. The second mutant was designed based on a previous report claiming that a particular polymorphic residue in the TRAV12-2 chain was stabilizing the TcR. We created a DMF5 mutant for this residue and showed that, unexpectedly, this TcR had acquired a reduced overall activity although the TcR-pMHC complex was more stable when compared to the TcR wild type complex (increased t1/2). In addition, the soluble TcR form of this mutant bound target cells less efficiently. From this we concluded that kinetic parameters do not always predict the superior functionality of mutant TcRs.
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Fitsum G
authors.initials: FG
authors.lastname: Tadesse
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy and K.G. Jebsen Center for Inflammation Research, Institute for Clinical Medicine, University of Oslo, Norway.
authors.forename: Nadia
authors.initials: N
authors.lastname: Mensali
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Lars-Egil
authors.initials: LE
authors.lastname: Fallang
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Even
authors.initials: E
authors.lastname: Walseng
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy and K.G. Jebsen Center for Inflammation Research, Institute for Clinical Medicine, University of Oslo, Norway.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; K.G. Jebsen Center for Cancer Immunotherapy and K.G. Jebsen Center for Inflammation Research, Institute for Clinical Medicine, University of Oslo, Norway.
authors.forename: Johanna
authors.initials: J
authors.lastname: Olweus
authors.affiliation: Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway; Department of Cellular Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway. Electronic address: sebastw@rr-research.no.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D002460:Cell Line; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008545:Melanoma / Q000276:immunology; D009154:Mutation / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D010641:Phenotype; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: Antigen; Peptide; Peptide-HLA complex; Soluble TcR; T-cell receptor; TcR; sTcR