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Single Molecule Force Spectroscopy Reveals Distinctions in Key Biophysical Parameters of αβ T-Cell Receptors Compared with Chimeric Antigen Receptors Directed at the Same Ligand


Banik DDebasis , Hamidinia MMaryam , Brzostek JJoanna , Wu LLing , Stephens HMHannah M , MacAry PAPaul A , Reinherz ELEllis L , Gascoigne NRJNicholas R J , Lang MJMatthew J . The journal of physical chemistry letters. 2021 8 4; 12(31). 7566-7573


Chimeric antigen receptor (CAR) T-cell therapies exploit facile antibody-mediated targeting to elicit useful immune responses in patients. This work directly compares binding profiles of CAR and αβ T-cell receptors (TCR) with single cell and single molecule optical trap measurements against a shared ligand. DNA-tethered measurements of peptide-major histocompatibility complex (pMHC) ligand interaction in both CAR and TCR exhibit catch bonds with specific peptide agonist peaking at 25 and 14 pN, respectively. While a conformational transition is regularly seen in TCR-pMHC systems, that of CAR-pMHC systems is dissimilar, being infrequent, of lower magnitude, and irreversible. Slip bonds are observed with CD19-specific CAR T-cells and with a monoclonal antibody mapping to the MHC α2 helix but indifferent to the bound peptide. Collectively, these findings suggest that the CAR-pMHC interface underpins the CAR catch bond response to pMHC ligands in contradistinction to slip bonds for CARs targeting canonical ligands.