Abstract
Antigen recognition by T cells relies on the interaction between T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) at the interface between the T cell and the antigen presenting cell (APC). The pMHC-TCR interaction is two-dimensional (2D), in that both the ligand and receptor are membrane-anchored and their movement is limited to 2D diffusion. The 2D nature of the interaction is critical for the ability of pMHC ligands to trigger TCR. The exact properties of the 2D pMHC-TCR interaction that enable TCR triggering, however, are not fully understood. Here, we altered the 2D pMHC-TCR interaction by tethering pMHC ligands to a rigid plastic surface with flexible poly(ethylene glycol) (PEG) polymers of different lengths, thereby gradually increasing the ligands’ range of motion in the third dimension. We found that pMHC ligands tethered by PEG linkers with long contour length were capable of activating T cells. Shorter PEG linkers, however, triggered TCR more efficiently. Molecular dynamics simulation suggested that shorter PEGs exhibit faster TCR binding on-rates and off-rates. Our findings indicate that TCR signaling can be triggered by surface-tethered pMHC ligands within a defined 3D range of motion, and that fast binding rates lead to higher TCR triggering efficiency. These observations are consistent with a model of TCR triggering that incorporates the dynamic interaction between T cell and antigen-presenting cell.
Highlights
T cells recognize antigens through the binding between T cell receptors (TCRs) and peptide-major histocompatibility complexes at the interface between T cell and antigen presenting cells (APCs). pMHC-TCR binding triggers TCR signaling that activates T cells
To tether pMHC ligands to a surface using poly(ethylene glycol) (PEG) linkers, we first conjugated pMHC with a PEG polymer, tethered the pMHC-PEG conjugates onto a plastic surface through biotinstreptavidin interactions (Fig. 1)
To investigate how 2D pMHC-TCR interaction contributes to TCR triggering, we gradually increased the range of motion of pMHC ligands in the third dimension using flexible PEG polymers
Summary
T cells recognize antigens through the binding between T cell receptors (TCRs) and peptide-major histocompatibility complexes (pMHCs) at the interface between T cell and antigen presenting cells (APCs). pMHC-TCR binding triggers TCR signaling that activates T cells. PMHC-TCR binding triggers TCR signaling that activates T cells. The binding between pMHC and TCR, can only occur when the two plasma membranes are brought together through cell-cell contact and are closely aligned by adhesion molecules. The T cell-APC interaction is dynamic and their relative motion inevitably applies mechanical stress to the interacting membranes and pMHC-TCR binding. Several models of TCR triggering have been proposed by taking into consideration certain features of the complex 2D pMHC-TCR interaction. The kinetic segregation model of TCR triggering, for example, proposes that the closely aligned membranes create steric barriers that segregate surface molecules based on their size [3]. The receptor deformation model, on the other hand, postulates that the binding between membrane-anchored pMHC and TCR transfers mechanical forces associated with cell locomotion to the TCR/CD3 complex
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