Mechanical forces impair antigen discrimination by reducing differences in T-cell receptor/peptide-MHC off-rates

Area of Science:

• Immunology
• Biophysics
• Cellular Mechanics

Background:

• T cells (T lymphocytes) utilize T-cell receptors (TCRs) to differentiate between self and foreign peptide-major-histocompatibility complexes (pMHCs).
• Discrimination is primarily based on the TCR/pMHC off-rate, but the role of mechanical forces in this process is debated.
• T cells generate forces during TCR/pMHC interactions, influencing binding dynamics.

Purpose of the Study:

• To investigate the impact of mechanical force on the off-rate of various TCR/pMHC interactions.
• To elucidate the mechanisms underlying TCR/pMHC bond strengthening or weakening under force.
• To understand how mechanical forces contribute to T cell antigen discrimination.

Main Methods:

• Experimental measurement of TCR/pMHC off-rates under varying mechanical forces.
• Molecular dynamics simulations to model TCR/pMHC interactions at the molecular level.
• Characterization of specific TCR/pMHC bonds, including the OT-I TCR/pMHC interaction.

Main Results:

• Lower-affinity TCR/pMHCs with faster solution off-rates exhibited greater resistance to mechanical force (weak slip or catch bonds).
• Higher-affinity TCR/pMHCs behaved as strong slip bonds, weakening under force.
• The well-known catch bond of the OT-I TCR/pMHC was confirmed to have low affinity and a fast solution off-rate.
• Molecular dynamics simulations corroborated the experimental findings.

Conclusions:

• Mechanical forces can strengthen weak TCR/pMHC interactions, enhancing antigen discrimination.
• Reducing force on TCR/pMHC interactions may improve discrimination between self and foreign antigens.
• Adhesion receptors CD2 and LFA-1 might play a role in force-shielding TCR/pMHC interactions, modulating T cell responses.