Parsing digital or analog TCR performance through piconewton forces

Area of Science:

• Immunology
• Molecular Biology
• Biophysics

Background:

• Alpha-beta T cell receptors (TCRs) recognize peptide-MHC complexes (pMHCs) on target cells.
• TCR-pMHC bond mechanics are critical for immune surveillance specificity and sensitivity.

Purpose of the Study:

• Investigate the mechanobiology of TCRs responding to varying antigen densities.
• Determine the functional differences between TCRs recognizing abundant versus sparse epitopes.

Main Methods:

• Utilized optical tweezers to study TCR-pMHC interactions in vitro and in vivo.
• Analyzed TCR responses to influenza A virus-derived epitopes (NP366-374/Db and PA224-233/Db).

Main Results:

• Observed both analog and digital activation patterns in CD8 T cells recognizing NP epitopes.
• Demonstrated that PA epitope-recognizing TCRs exclusively exhibit digital behavior with enhanced bond lifetimes.
• Digital TCR performance correlated with in vivo and in vitro activation markers.

Conclusions:

• Digital TCR activation, requiring fewer ligands, is superior for immune responses.
• Digital TCRs are likely essential for developing effective immunotherapies targeting neoantigens.