Asymmetric framework motion of TCRαβ controls load-dependent peptide discrimination

Area of Science:

• Immunology
• Biophysics
• Computational Biology

Background:

• Mechanical force is crucial for T cell receptor (TCR) and peptide-MHC interactions initiating T cell activation.
• The precise mechanism by which mechanical forces influence TCR-pMHC binding and T cell response remains incompletely understood.

Purpose of the Study:

• To investigate the role of mechanical force in TCR-pMHC complex dynamics and T cell activation.
• To elucidate the molecular mechanisms underlying peptide discrimination by TCRs under varying mechanical loads.

Main Methods:

• All-atom molecular dynamics simulations were employed to study the A6 TCR complexed with HLA-A*02:01 presenting agonist and antagonist peptides.
• Simulations were performed under varying mechanical extensions to mimic applied load, and analyses focused on inter-chain movements and interfacial contacts.

Main Results:

• TCR alpha and beta chains exhibit asymmetric movements, significantly impacting the TCR-pMHC interface, especially the peptide-sensing CDR3 loops.
• The TCR-pMHC complex demonstrates load-dependent stabilization with agonist peptides, whereas antagonist peptides lead to destabilization.
• Simulations involving a Cβ FG-loop deletion mutant and in silico mutant peptides corroborated the findings regarding mechanical response and peptide discrimination.

Conclusions:

• Interdomain motion, fluctuating forces, and interfacial contacts collectively determine the mechanical response of the TCR-pMHC complex.
• These factors are essential for TCRs to achieve fine peptide discrimination, resolving discrepancies between crystal structures of agonist and antagonist complexes.