Dynamically Mechano-regulation Of TCR Antigen Rccognition And Immune Receptor CTLA-4/ligands Interactions

CD8+ T cells use TCRs to specially recognize and interact with foreign or tumor neoantigen-pMHCs on target cells to activate CD8+T cell cytotoxicity and adaptive immunity.CD8s on T cell surface work as co-receptors to stabilize TCR-pMHC-1 interactions and enhance TCR antigen recognition and TCR signals,while the coinhibitory receptor CTLA-4 can mediate inhibitory signals by interacting with CD80/86 to inhibit TCR signals.Many evidences showed that biomechanical force can prolong pMHC-I/TCR bond lifetimes to form antigen specific catch bonds which enhance the potency of TCR antigen recognition and T cell activation.However,the detailed mechano-chemical coupled mechanism of TCR antigen recognition still remains unclear.Whether biomechanical force can affect CD8 and CTLA-4 to regulate their biological functions.We found that biomechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force,resulting in TCR-pMHC catch bonds and T cell activation.Under force,mechanical pulling on TCR-pMHC-I complex can induce rotational conformational changes of α1-α2 domains in MHC-I by disrupting the intramolecular interactions between(32 microglobulin and α3 or α1-α2 domains.This rotation enhances TCR-pMHC-I binding by forming new hydrogen bonds within the interface between TCR and pMHC-I.Intriguingly,cancer associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC-I catch bonds.Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes.We also found that biomechanical force can induce different conformations of CD8 to regulate TCR antigen recognition.When pMHC-I al-a2 domains rotate,biomechanical force induces the conformational changes of CD8 extracellular domains which form new interactions with pMHC-I α1-α2 domains to resist the dissociation of CD8 from pMHC-I and enhance TCR-pMHC-I catch bonds and TCR antigen recognition.In addition,we foud that biomechanical force also can regulate the interaction of coinhibitory receptor CTLA-4 with its ligand CD80/86.In clinical,CTLA-4 Y104C mutation can greatly shorten the force-dependent bond lifetime of CTLA-4 with CD80,but not CD86.This may lead to the activation of the whole immune system and autoimmune disease in patient.In summary,our findings demonstrate that biomechanical force can enhance TCR-pMHC-I catch bonds and the potency of TCR antigen recognition by inducing the conformational changes of pMHC-I and CD8.Our work reveals the mechano-chemical coupled regulation of TCR antigen recognition and its relationship with T cell functions.In autoimmune dieases,our data indicate that biomechanical force can maintain the homeostasis of immune system by regulating CTLA-4/CD80 interactions.Our findings may provide new insights,thoughts,methods and basic theory to advance our understanding of mechano-immunology and to potentially benefit clinical immunotherapy.