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

J Immunol. 2010 May 1;184(9):4936-46. doi: 10.4049/jimmunol.1000173. Epub 2010 Mar 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Antigens, Neoplasm
  • CTAG1B protein, human
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Membrane Proteins
  • Neoplasm Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • peptide NY-ESO-1 157-165