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 complex’s 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 α ₃ domain applies restraints to the latter one, which leads the MHC α 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.