title: Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.
abstract: 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.
authors.affiliation: Multidisciplinary Oncology Center, Lausanne University Hospital, Switzerland.
authors.forename: Daphné A
authors.initials: DA
authors.lastname: Schmid
authors.forename: Melita B
authors.initials: MB
authors.lastname: Irving
authors.forename: Vilmos
authors.initials: V
authors.lastname: Posevitz
authors.forename: Michael
authors.initials: M
authors.lastname: Hebeisen
authors.forename: Anita
authors.initials: A
authors.lastname: Posevitz-Fejfar
authors.forename: J-C Floyd
authors.initials: JC
authors.lastname: Sarria
authors.forename: Raquel
authors.initials: R
authors.lastname: Gomez-Eerland
authors.forename: Margot
authors.initials: M
authors.lastname: Thome
authors.forename: Ton N M
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C504237:peptide NY-ESO-1 157-165