Tuning the sensitivity of mechanosensory receptors through histidine scanning

Area of Science:

• Immunology
• Molecular Biology
• Biotechnology

Background:

• T cell receptor (TCR)-T cell therapy shows promise for solid tumors but faces challenges in identifying potent and specific TCRs.
• Conventional affinity maturation techniques can lead to severe off-target toxicity.
• The role of catch bonds in TCR signaling and their potential to improve TCR-T therapy remains largely unexplored.

Purpose of the Study:

• To investigate the formation of catch bonds in TCRs and their potential to mitigate challenges in TCR-T cell therapy.
• To develop a novel method for engineering low-affinity, high-potency TCRs for enhanced safety and efficacy.

Main Methods:

• Histidine scanning was employed to identify TCR hotspots capable of forming additional catch bonds.
• Randomization of identified hotspots created TCR libraries for screening low-affinity, high-potency variants.
• The mechanism of histidine in facilitating catch bond formation and intracellular signaling was investigated.

Main Results:

• Histidine scanning successfully identified TCR hotspots that promote catch bond formation.
• Engineered TCRs specific for various antigens demonstrated high potency without off-target or on-target toxicity.
• Histidine was found to facilitate hydrogen bonds and salt bridges, fortifying the intracellular signaling cascade.

Conclusions:

• Histidine scanning provides a universal method for engineering safe, low-affinity, high-potency TCRs for TCR-T cell therapy.
• This approach eliminates the need for structural information in designing TCR libraries.
• Histidine scanning has broad applicability to other mechanosensory ligand-receptor systems.