PMHC ligand anchored on a plastic surface via a 61 nm flexible poly(ethylene glycol) linker triggers the TCR: implications for the mechanism of TCR signal initiation (35.18)

Abstract

Abstract A critical step in the immune response is signal initiation from the T cell antigen receptor (TCR) by its ligand, peptide antigen presented by the major histocompatibility complex (pMHC). How TCR is triggered by ligand binding is still unclear. An interesting aspect of the puzzle is the sharp contrast between the inability of soluble pMHC to trigger TCR and the high triggering efficiency of surface-anchored pMHC. Here, we investigate the boundary between soluble and surface-anchored pMHC by anchoring pMHCs on plastic surfaces via poly(ethylene glycol) (PEG) linkers of varying length. We found that pMHCs anchored on the surface via a 61 nm linker trigger TCR as efficiently as a much shorter 5.6 nm linker. The lack of negative impact on TCR triggering by the long linker does not support the kinetic segregation model of TCR triggering, in which the critical factor is the shortness of the pMHC-TCR bridge between the membranes of T cell and antigen presenting cell (APC). Our result supports the idea that TCR triggering does not require receptor cross-linking, since the length of the linker far exceeds the distance required for two pMHC molecules to cross-link the TCR. Furthermore, this result is consistent with the receptor deformation model - a long linker may be tolerated as long as the T cell and APC membranes detach to a distance greater than the length of the pMHC-TCR bridge, such that mechanical force can still be applied to the TCR. Work supported by NIH R21 AI078387, Joseph L. Hollander Chair, and Joseph Stokes Jr. Res. Inst.