Evidence that the Density of Self Peptide-MHC Ligands Regulates T-Cell Receptor Signaling

Abstract

Noncognate or self peptide-MHC (pMHC) ligands productively interact with T-cell receptor (TCR) and are always in a large access over the cognate pMHC on the surface of antigen presenting cells. We assembled soluble cognate and noncognate pMHC class I (pMHC-I) ligands at designated ratios on various scaffolds into oligomers that mimic pMHC clustering and examined how multivalency and density of the pMHCs in model clusters influences the binding to live CD8 T cells and the kinetics of TCR signaling. Our data demonstrate that the density of self pMHC-I proteins promotes their interaction with CD8 co-receptor, which plays a critical role in recognition of a small number of cognate pMHC-I ligands. This suggests that MHC clustering on live target cells could be utilized as a sensitive mechanism to regulate T cell responsiveness.

In vitro controlled release of antigen in dendritic cells using pH-sensitive liposome-polymeric hybrid nanoparticles

“…To prime naive T cells, there has to be a sufficient number of interactions between T cell receptors and pMHC complexes. Higher density of pMHC complexes may thus increase the likelihood of such interactions [31]. Therefore, burst release of antigen from pH-sensitive hybrid NPs in DCs may promote the magnitude of immune response.…”

Binding of TCR Multimers and a TCR-Like Antibody with Distinct Fine-Specificities Is Dependent on the Surface Density of HLA Complexes

“…The avidity gained through tetramerization of our Env183/A2-specific TCR allowed the tetramers to bind beads as well as the Env183/A2 mAb when saturated with the correct pMHC. The sensitivity of our TCR tetramer staining was clearly dependent on the degree of packing of pMHC on the beads, presumably because at higher density the TCR tetramer can bind clusters of pMHC simultaneously [16], [52], [53]. This reliance of TCR tetramers on the pMHC density has been observed in cellular experiments as well, where the staining intensity decreased proportionally with the titration of cognate pMHC ligand [14].…”

Linking form to function: Biophysical aspects of artificial antigen presenting cell design

“…In a separate liposome-based study, CD4 stimulation was significantly stronger from aAPC presenting clustered compared to unclustered MHC [154]. A high density (5–8 nm separating distances) of clustered non-cognate MHC presented on the surface of nano-sized quantum dots is required to enhance binding and activation by cognate pMHC [155], a finding that may explain conflicting results obtained with the “pseudo-dimer” theory, which states that numerous weak binding events with non-cognate MHC augment less frequent strong binding events mediated by cognate MHC.…”