Schmid, Daphne A.Irving, Melita B.Posevitz, VilmosHebeisen, MichaelPosevitz-Fejfar, AnitaSarria, J-C. FloydGomez-Eerland, RaquelThome, MargotSchumacher, Ton N. M.Romero, PedroSpeiser, Daniel E.Zoete, VincentMichielin, OlivierRufer, Nathalie2011-12-162011-12-162011-12-16201010.4049/jimmunol.1000173https://infoscience.epfl.ch/handle/20.500.14299/75555WOS:000277093000045Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A*0201/NY-ESO-1(157-165) specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K-D < similar to 5 mu M), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity. The Journal of Immunology, 2010, 184: 4936-4946.Free-Energy DecompositionPhage DisplayPeptide-MhcSignal-TransductionDirected EvolutionBinding-PropertiesReceptor RequiresCancer RegressionIn-VitroMm-Gbsatext::journal::journal article::research article