Biology subjects

Travaglino, S.

Publications and source records attributed to Travaglino, S..

4 recordsLinked to original sources

bioRxiv2025

Evaluating the effects of CD8/CD4 on T cell function in terms of TCR-pMHC-coreceptor catch and slip bonds

BackgroundT cells interact with peptide-major histocompatibility complex (pMHC) via the T cell receptor (TCR) and coreceptor CD4 or CD8 depending on the MHC class. These interactions form catch and slip bonds depending on the pMHC activity. Coreceptors and bond profiles impact TCR triggering and antigen discrimination. MethodsBuilt upon our recent correlative analysis of TCR-pMHC catch bond with T cell function, we analyzed 26 pairs of T-cell-pMHC interactions to compare the correlations of their biophysical metrics with antigen-induced T cell responses in two situations: when the coreceptor is prevented vs permitted to bind pMHC. ResultsWe found that the force-based metrics of TCR bond with pMHC perform better than parameters measured in the absence of force either in situ at the T cell membrane or in fluid phase using purified ectodomain proteins as predictors of T cell activation and thymocyte selection in both cases when the contributions of coreceptors are absent and present. Moreover, CD8 or CD4 co-engagement with pMHC systematically increases these metrics and increases TCR sensitivity and specificity, indicating coreceptor-mediated amplification of, or conversion to, catch-bonds that enhances mechanical tuning of TCR responses. ConclusionOur findings highlight the importance of force in antigen recognition by the TCR and reveal that parameters derived from the bond profile, especially in the presence of coreceptor, are more informative predictors of T cell activation compared to conventional affinity-based measurements. These results offer mechanistic insights into the roles of catch bonds and coreceptors in TCR antigen recognition.

immunology↗

bioRxiv2023

Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome

B cell maturation in germinal centers (GCs) depends on cognate interactions between the T and B cells. Upon interaction with CD40 ligand (CD40L) on T cells, CD40 delivers co-stimulatory signals alongside B cell antigen receptor (BCR) signaling to regulate affinity maturation and antibody class-switch during GC reaction. Mutations in CD40L disrupt interactions with CD40, which lead to abnormal antibody responses in immune deficiencies known as X-linked Hyper IgM syndrome (X-HIgM). Assuming that physical interactions between highly mobile T and B cells generate mechanical forces on CD40-CD40L bonds, we set out to study the B cell mechanobiology mediated by CD40-CD40L interaction. Using a suite of biophysical assays we find that CD40 forms catch bond with CD40L where the bond lasts longer at larger forces, B cells exert tension on CD40-CD40L bonds, and force enhances CD40 signaling and antibody class-switch. Significantly, X-HIgM CD40L mutations impair catch bond formation, suppress endogenous tension, and reduce force-enhanced CD40 signaling, leading to deficiencies in antibody class switch. Our findings highlight the critical role of mechanotransduction in CD40 function and provide insights into the molecular mechanisms underlying X-HIgM syndrome.

immunology↗

bioRxiv2022

Cooperative ectodomain interaction among TCRαβ, CD3γε, and CD3δε enhances TCR mechanotransduction

TCR signaling poses a mechanical problem: pMHC binding occurs at the TCR{beta} ectodomain (ECD) head, whereas ITAM phosphorylation occurs on CD3 cytoplasmic tails. Chemistry cannot bridge this >10 nm gap, requiring the two events to be coupled through the TCR-CD3 interface, thus involving conformational allostery and being regulatable by force. Although weak ECD cis-interactions between TCR{beta} and CD3 have been proposed to contribute to this coupling, their kinetics and mechanical competence remain elusive. Here, we quantify TCR{beta}-CD3 ECD cis-interactions in a pseudo-cis configuration using two-dimensional binding and single-bond force spectroscopy, finding that TCR{beta}-CD3{gamma}{varepsilon} and TCR{beta}-CD3{delta}{varepsilon} interactions have low affinity and rapid kinetics, yet form catch bonds. Critically, concurrent engagement of CD3{gamma}{varepsilon} and CD3{delta}{varepsilon} produces high cis-cooperativity, yielding a stronger and longer-lasting CD3{gamma}{varepsilon}-TCR{beta}-CD3{delta}{varepsilon} trimolecular catch bond than the sum of the two dimeric bonds, with force-stabilized lifetimes matching those of agonist TCR-pMHC trans-interaction. Molecular dynamics simulations reveal an expanded, cooperative, and asymmetric contact network, making CD3{delta}{varepsilon} more force-responsive and susceptible to conformational change than CD3{gamma}{varepsilon}. Interface mutations do not alter force-free affinities but remodel cooperative cis-bond profiles, leading to an inverse correlation with trans-bond profiles and T cell signaling. These results identify cooperative ECD cis-interaction as a mechanically regulatable allosteric coupling element at the TCR-CD3 junction important to antigen recognition and signal initiation.

immunology↗

bioRxiv2021

Cooperative binding of TCR and CD4 to pMHC enhances TCR sensitivity

Antigen recognition of CD4+ T cells by the T cell receptor (TCR) can be greatly enhanced by the coreceptor CD41-7. Yet, understanding of the molecular mechanism is hindered by the ultra-low affinity of CD4 binding to class-II peptide-major histocompatibility complexes (pMHC)1,7-10. Using two-dimensional (2D) mechanical-based assays, we determined a CD4-pMHC interaction to have 3-4 logs lower affinity than cognate TCR-pMHC interactions8, and to be susceptible to increased dissociation by forces (slip bond)5,8,11. In contrast, CD4 binds TCR-prebound pMHC at 3-6 logs higher affinity, forming TCR-pMHC-CD4 trimolecular bonds that are prolonged by force (catch bond)5,8,11 and modulated by protein mobility on the cell membrane, indicating profound TCR-CD4 cooperativity. Consistent with a tri-crystal structure12, using DNA origami as a molecular ruler to titrate spacing between TCR and CD4 indicates that 7-nm proximity optimizes trimolecular bond formation with pMHC. Our results reveal how CD4 augments TCR antigen recognition.

immunology↗