The receptor deformation model of TCR triggering

Abstract

Signal initiation from the T cell antigen receptor (TCR) by its ligand, peptide antigen presented by major histocompatibility complex (pMHC), is a critical step in immune responses. How TCR is “triggered” by ligand binding is still unclear. Using lipid bilayer and plastic based artificial antigen presenting systems, we demonstrate that TCR can be triggered by a very low number (<10) of monomeric agonist pMHCs anchored on a surface. TCR triggering was not dependent on the presence of endogenous pMHCs. It was, however, critically dependent on active T cell adhesion to the surface and intact actin cytoskeleton function. Based on these observations, and the dynamic T cell/APC interaction observed in vivo by other groups, we propose the receptor deformation model of TCR triggering. In this model, TCR signaling is initiated by conformational changes of the TCR/CD3 complex, induced by a pulling force originating from the cytoskeleton, and transmitted through pMHC‐TCR binding interactions with enough strength to resist rupture. The increased dissociation rate of pMHC‐TCR interaction under force should facilitate fast and efficient TCR serial triggering by a single agonist pMHC, thus explaining the sensitivity of TCR triggering. This model also offers “pMHC‐TCR binding strength under force” as the parameter that defines the specificity of TCR triggering, i.e., the ability and potency of certain pMHCs to trigger TCR.