Multiscale Synaptic Dynamics of T-Cell Antigen Recognition

Abstract

T-cell antigen recognition plays an essentially important role in adaptive immunity, enabling pathogen clearance and the elimination of abnormal cells. Recent studies have identified the force-dependent property of TCR–pMHC (TM) bonds as a key for antigen recognition, with the lifetimes of individual TM bonds being central to TCR signaling. However, it remains unclear how multiple TM bonds cooperate each other within the immune synapses to regulate T-cell activation. To this end, we establish a multiscale mechano-chemo-biological model of T-cell antigen recognition by integrating force-dependent bond dissociation, interfacial molecular reorganization, and cluster-enhanced TCR signaling. This model reveals how the multiscale dynamics at the immune synapse, modulated by force-dependent bonds, reproduces TCR-mediated activation behaviors. We find a phase-like transition in T-cell activation that arises from distinct synaptic dynamics, with robust TM engagement and TCR clustering sustaining signaling-competent adhesion and weak synaptic dynamics leading to ineffective adhesion. Mechanistically, immune synaptic strength emerges from the cooperative dynamics of multiple bonds within TCR clusters and may contribute to the mechanical threshold of this transition. Furthermore, it is discovered that T cells exhibit two stiffness-sensing modes, depending on the distinct TM-bond properties. Monotonic enhancement is supported by stiffness-enhanced TCR clustering, whereas biphasic regulation arises when TCR clustering is disrupted by bond rupture at high stiffness. This work not only helps understand the microscopic mechanisms of T-cell antigen recognition, but also offers fundamental principles for mechanically tuning T-cell functions.