CD8⁺ T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold

Area of Science:

• Immunology
• Molecular Biology
• Biophysics

Background:

• The CD8 co-receptor is crucial for CD8+ T-cell immunity, enhancing sensitivity to antigen-driven activation through interaction with peptide-MHC class I (pMHCI) molecules.
• This interaction occurs at a site distinct from the T-cell receptor (TCR) binding platform, modulating the threshold for T-cell activation.
• Even minor increases in pMHCI/CD8 interaction strength can disproportionately amplify antigen sensitivity, but higher affinities risk losing recognition specificity.

Purpose of the Study:

• To investigate the relationship between pMHCI/CD8 binding affinity and TCR-mediated antigen specificity.
• To determine the affinity threshold at which antigen recognition is maintained.
• To explore the potential for engineering CD8-binding properties to enhance adoptive T-cell transfer efficacy.

Main Methods:

• Utilized a panel of MHC class I (MHCI) mutants engineered to possess altered CD8-binding properties.
• Assessed the impact of varying pMHCI/CD8 affinities on TCR-mediated antigen specificity and T-cell activation sensitivity.
• Quantified the biophysical parameters of pMHCI/CD8 interactions.

Main Results:

• Demonstrated that TCR-mediated antigen specificity is contingent upon a defined pMHCI/CD8 affinity threshold.
• Showed that small increases in pMHCI/CD8 interaction strength (~1.5-fold) can enhance antigen sensitivity significantly (up to two orders of magnitude).
• Found that substantially higher affinities (~10-fold) lead to a complete loss of recognition specificity.

Conclusions:

• CD8 co-receptor binding affinity to pMHCI plays a critical role in maintaining antigen specificity.
• Engineering CD8-binding properties within specific biophysical limits can enhance T-cell sensitivity without sacrificing specificity.
• These findings suggest a strategy for improving the therapeutic efficacy of adoptive T-cell transfer by optimizing CD8/pMHCI interactions.