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

Area of Science:

• Immunology
• T cell biology
• Cancer immunotherapy

Background:

• Adaptive immune responses depend on T cell receptors (TCRs) recognizing peptide-MHC complexes.
• Tumor-specific TCRs often have low affinity, limiting their therapeutic potential.
• Understanding the relationship between TCR binding affinity and T cell function is vital for designing effective immunotherapies.

Purpose of the Study:

• To precisely evaluate the correlation between TCR-peptide-MHC binding parameters and T cell functional outcomes.
• To identify an optimal affinity threshold for TCRs in cancer immunotherapy.
• To guide the rational design of tumor-specific TCRs for enhanced efficacy and safety.

Main Methods:

• Generated sequence-optimized TCR variants with varying affinities for HLA-A(*)0201/NY-ESO-1(157-165).
• Transduced primary human CD8 T cells with these TCRs.
• Assessed TCR-peptide-MHC binding (affinity, avidity) and T cell functions (clustering, signaling, proliferation, lysis).

Main Results:

• Demonstrated robust correlations between TCR binding affinity/avidity and T cell responses.
• Identified a plateau in T cell function above a specific TCR-peptide-MHC affinity threshold (K(D) < ~5 μM).
• Observed that T cell function does not increase beyond this affinity threshold.

Conclusions:

• Maximal T cell function is achieved at a defined TCR-peptide-MHC affinity threshold.
• TCRs do not need to be optimized beyond this threshold for optimal function.
• Rational TCR design can achieve optimal T cell function while avoiding cross-reactivity risks.