CD8-mediated organization of the TCR-pMHC interface shapes its force response and dissociation pathways

The mechanical response of the interaction between the T cell receptor (TCR) and the peptide major histocompatibility complex (pMHC) is fundamental to antigen recognition, but the atomic-scale mechanisms by which the CD8 coreceptor modulates the complexs conformational states and force-bearing behavior remain poorly understood. We employed all-atom molecular dynamics and steered molecular dynamics simulations of membrane-embedded TCR-pMHC and TCR-pMHC-CD8 complexes to characterize their dynamics and force-induced dissociation. Microsecond-long molecular dynamics (MD) simulations show that binding of CD8 to the MHC 3 domain applies restraints to the latter one, which leads the MHC 1 helix to stably bind against the TCR complementarity-determining regions (CDRs) and suppresses the fluctuations of the antigenic peptide. Furthermore, under mechanical loading, the TCR-pMHC-CD8 system exhibits a distinct dissociation pathway compared to that of TCR-pMHC complex, which may strengthen the mechanical stability of the binding of TCR-pMHC. Collectively, these findings unravel the molecular mechanisms of CD8-mediated synergistic stabilization and mechanical regulation of TCR-pMHC, providing new mechanistic insights into coreceptor-dependent T cell antigen recognition. SIGNIFICANCEThe TCR-pMHC handshake is the definitive spark that ignites the immune response. It has been shown that the force applied to the TCR-pMHC complex is critical for triggering the downstream signaling. In addition, TCR recognition of pMHC is regulated by force and strongly influenced by coreceptors, such as CD8. Therefore, understanding how coreceptors mediate TCR-pMHC interactions upon the application of force is crucial for revealing the biophysical basis of immune signaling. This study unravels how coreceptors shape the dynamics and mechanical response of the TCR-pMHC complex at the atomic level.