TCR catch bonds nonlinearly control CD8 cooperation to shape T cell specificity

Area of Science:

• Immunology
• Biophysics
• Structural Biology

Background:

• Naturally evolved T-cell receptors (TCRs) distinguish self from non-self antigens with high specificity, a trait often lost in engineered high-affinity TCRs, leading to toxicity.
• The mechanistic basis for this difference in specificity between natural and engineered TCRs remains poorly understood.

Purpose of the Study:

• To elucidate the mechano-chemical mechanisms underlying the specificity of natural TCRs compared to engineered TCRs.
• To investigate the role of mechanical force and CD8 coreceptor in TCR-pMHC interactions.
• To develop methods for identifying and engineering TCRs with improved specificity and reduced off-target effects.

Main Methods:

• Investigated TCR-pMHC interactions under varying mechanical forces.
• Analyzed TCR-pMHC binding kinetics and conformational changes using biophysical techniques.
• Developed force-dependent TCR-pMHC kinetics-function maps.

Main Results:

• Natural TCRs form optimal catch bonds with antigens by exploiting mechanical force, facilitated by a flexible binding interface and force-enhanced CD8 binding.
• Engineered high-affinity TCRs exhibit rigid interfaces, hindering force-induced conformational changes and optimal catch-bond formation.
• Engineered TCRs can form moderate catch bonds with non-cognate antigens, causing cross-reactivity and reduced specificity.

Conclusions:

• Mechanical force is crucial for the specificity of natural TCRs, enabling optimal catch-bond formation and CD8 engagement.
• TCR rigidity in engineered variants compromises specificity and leads to off-target toxicity.
• Force-dependent kinetics-function maps can guide the engineering of safer and more effective TCRs for immunotherapy.