The receptor deformation model of TCR triggering

Abstract

Through T cell receptors (TCRs), T cells can detect and respond to very small numbers of foreign peptides among a huge number of self-peptides presented by major histocompatibility complexes (pMHCs) on the surface of antigen-presenting cells (APCs). How T cells achieve such remarkable sensitivity and specificity through pMHC-TCR binding is an intensively pursued issue in immunology today; the key question is how pMHC-TCR binding initiates, or triggers, a signal from TCRs. Multiple competing models have been proposed, none of which fully explains the sensitivity and specificity of TCR triggering. What has been omitted from existing theories is that the pMHC-TCR interaction at the T cell/APC interface must be under constant mechanical stress, due to the dynamic nature of cell-cell interaction. Taking this condition into consideration, 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. By introducing mechanical force into a model of T cell signal initiation, the receptor deformation model provides potential mechanistic solutions to the sensitivity and specificity of TCR triggering.

Figure 1

The schematics of the receptor deformation model of TCR triggering. A) Interaction of pMHCs and TCRs at the close membrane-membrane contact site of the T cell/APC interface. Large adhesion molecules such as LFA-1 and ICAM-1 bring together the cell membranes, which are further aligned by small adhesion molecules such as CD2 and CD48, to a distance permitting pMHC-TCR interaction. The interaction between agonist pMHC and TCR per se does not initiate TCR signaling. B) Forces generated from the cytoskeleton, which drive active T cell movement relative to APC and T cell morphological changes, detach the T cell plasma membrane from the APC. Part of the force is delivered to the TCR/CD3 complex through pMHC-TCR binding. Binding between agonist pMHC and TCR is strong enough to deliver a force that deforms the TCR/CD3 complex to a conformation or configuration that can initiate an activation signal. Weak binding between self-pMHC and TCR breaks before such a force can be delivered. Such a binding could, however, deliver a weak force that causes minor receptor deformation, leading to a survival signal. The detaching force could also deform the MHC molecule to a conformation that binds coreceptors with higher affinity, or directly deform the coreceptors to alter the activity of associated tyrosine kinase Lck.