Catch Bonds Nonlinearly Control CD8 Cooperation to Shape T Cell Specificity
T cell receptors (TCRs) play a crucial role in the immune system by recognizing antigen peptides presented by major histocompatibility complexes (MHCs), thereby initiating immune responses against pathogens and tumor cells. However, the specificity of TCRs—their ability to distinguish self-antigens from non-self antigens—is central to the effective functioning of the immune system. Although engineered high-affinity TCRs show potential in enhancing antigen recognition, they often lose specificity, leading to cross-reactivity with self-antigens and causing severe side effects. The mechanism behind this phenomenon remains unclear, hindering the application of TCRs in cancer immunotherapy and infectious disease treatment.
Naturally evolved TCRs exhibit extremely high specificity under dynamic biomechanical regulation, while engineered high-affinity TCRs often lose this specificity. This study aims to reveal how natural TCRs utilize mechanical forces to form optimal “catch bonds” and to explore the mechanisms behind the loss of specificity in high-affinity TCRs. By investigating the interactions between TCRs and peptide-MHC complexes (pMHCs), the research team hopes to provide a theoretical foundation for designing safer and more effective TCR therapies.
Source of the Paper
This paper was co-authored by Rui Qin, Yong Zhang, Jiawei Shi, and 12 other researchers from institutions such as Zhejiang University, Institute of Biophysics, Chinese Academy of Sciences, and Zhengzhou University. The paper was published online on February 27, 2025, in the journal Cell Research, titled “TCR catch bonds nonlinearly control CD8 cooperation to shape T cell specificity.”
Research Process and Results
1. Mechano-regulation of TCR-pMHC Interactions
The research team first used molecular dynamics (MD) simulations and single-molecule ultra-stable biomembrane force probe (U-BFP) experiments to study the interactions between TCRs and pMHCs under mechanical forces. The study found that natural TCRs form optimal catch bonds through mechanical forces, which rely on the mechanical flexibility of the TCR-pMHC binding interface. This flexibility allows mechanical forces to induce sequential conformational changes in MHC and CD8 molecules, thereby enhancing CD8 binding to MHC. In contrast, engineered high-affinity TCRs form rigid, tightly bound interfaces with pMHCs, hindering the mechanical force-induced conformational changes and preventing the formation of catch bonds.
2. Cross-reactivity Mechanism of High-Affinity TCRs
The study further revealed that although high-affinity TCRs can form moderate-strength catch bonds with non-stimulatory pMHCs, this binding leads to cross-reactivity with self-antigens, reducing TCR specificity. By constructing structural models of TCR-pMHC-CD8 ternary complexes, the research team demonstrated how mechanical forces regulate TCR specificity by inducing conformational changes in MHC and CD8. The rigid binding interface of high-affinity TCRs impedes these conformational changes, preventing CD8 from effectively enhancing TCR specificity.
3. The Role of CD8 in TCR Specificity
The research team also experimentally validated the critical role of CD8 in TCR specificity. By mutating the Ile2 residue of CD8β, they found that blocking the mechanical force-enhanced binding between CD8 and MHC significantly reduced TCR specificity. This result indicates that CD8 plays an important role in TCR specificity through mechanical force-induced conformational changes.
4. Construction of Kinetic-Function Maps
Based on the above findings, the research team constructed kinetic-function maps of TCR-pMHC interactions to distinguish functional from non-functional TCR-pMHC pairs and to identify TCRs with cross-reactivity risks. These maps integrate two-dimensional binding affinity, mechanical force-dependent bond lifetimes, and CD8 enhancement effects, providing an important tool for designing safer and more effective TCR therapies.
Conclusion and Significance
This study reveals the mechano-chemical basis of TCR specificity, elucidating how natural TCRs utilize mechanical forces and CD8 cooperation to achieve high specificity, and explaining the mechanisms behind the loss of specificity in high-affinity TCRs. The findings provide a critical theoretical foundation for designing safer and more effective TCR therapies, particularly in cancer immunotherapy and infectious disease treatment, by helping to reduce the risk of cross-reactivity with self-antigens.
Research Highlights
- Mechanical Force-Regulated Catch Bond Mechanism: The study found that natural TCRs form optimal catch bonds through mechanical forces, while the rigid binding interface of high-affinity TCRs hinders this process.
- Critical Role of CD8: The research highlights the important role of CD8 in TCR specificity through mechanical force-induced conformational changes.
- Kinetic-Function Maps: The research team constructed kinetic-function maps of TCR-pMHC interactions, providing a valuable tool for the design and optimization of TCR therapies.
Other Valuable Information
The study also explored the kinetic model of TCR specificity, proposing the “peak theory,” which suggests that CD8 cooperation is most effective when TCR-pMHC bond lifetimes fall within a medium mechanical force range. This theory offers a new perspective for understanding TCR specificity and sensitivity.
This research not only reveals the mechano-chemical basis of TCR specificity but also provides important theoretical foundations and practical tools for designing safer and more effective TCR therapies.