Abstract
SummaryThe mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCRαβ and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαβ cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation.
Highlights
T cell antigen receptor (TCR-CD3) signaling drives thymocyte maturation and T cell responses upon recognition of highly polymorphic major histocompatibility complex (MHC) proteins presenting myriad of short peptides (p) that originated from the degradation of self and foreign proteins (Stritesky et al, 2012)
Va and Vb are connected to Ig-like constant domains, namely, Ca and Cb, that are linked to the transmembrane regions (TMRs) through a stalk, called connecting peptide (CP). peptide-major histocompatibility complex (pMHC) binding is signaled intracellularly by four non-covalently associated subunits (g, d, ε, and z), called CD3, organized into three dimers, namely, gε, dε and zz, with the latter disulphide linked (Call et al, 2002). ε, g, and d exhibit an Ig-like extracellular domain (ECD) connected to TMRs by short CPs, whereas z features a z10-residuelong ECD
We found that soluble monomeric pMHC agonists reduce TCRCD3 quaternary structure cohesion and induce signal transduction, independently of co-receptor, clustering, or force
Summary
T cell antigen receptor (TCR-CD3) signaling drives thymocyte maturation and T cell responses upon recognition of highly polymorphic major histocompatibility complex (MHC) proteins presenting myriad of short peptides (p) that originated from the degradation of self and foreign proteins (Stritesky et al, 2012). Despite high physical and chemical diversity in binding interfaces, TCRCD3 ensures responses of exceptional specificity and sensitivity (Davis et al, 2007), with weak affinity (0.1–100 mM) and short half-life (t1/2) (
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
