Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function

• Published in: The Journal of immunology (1950) Vol. 184; no. 9; pp. 4936 - 4946
• Main Authors: Schmid, Daphné A, Irving, Melita B, Posevitz, Vilmos, Hebeisen, Michael, Posevitz-Fejfar, Anita, Sarria, J-C Floyd, Gomez-Eerland, Raquel, Thome, Margot, Schumacher, Ton N M, Romero, Pedro, Speiser, Daniel E, Zoete, Vincent, Michielin, Olivier, Rufer, Nathalie
• Format: Journal Article
• Language: English
• Published: United States 01.05.2010
• Subjects: Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Adhesion - genetics; Cell Adhesion - immunology; Cell Line; Cell Line, Transformed; Cell Line, Tumor; Cells, Cultured; Cytotoxicity, Immunologic - genetics; HLA-A Antigens - genetics; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; HLA-A2 Antigen; Humans; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Peptide Fragments - genetics; Peptide Fragments - metabolism; Protein Binding - genetics; Protein Binding - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000173

Protective 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) < approximately 5 muM), 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.