Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion

Abstract

Molecular crowding of agonist peptide/MHC class II complexes (pMHCIIs) with structurally similar, yet per se non-stimulatory endogenous pMHCIIs has been postulated to sensitize T-cells for the recognition of single antigens on the surface of dendritic cells and B-cells. When testing this premise with the use of advanced live cell microscopy, we observed pMHCIIs as monomeric, randomly distributed entities diffusing rapidly after entering the APC surface. Synaptic TCR-engagement of highly abundant endogenous pMHCIIs was low or non-existent and affected neither TCR-engagement of rare agonist pMHCII in early and advanced synapses nor agonist-induced TCR-proximal signaling. Our findings highlight the capacity of single freely diffusing agonist pMHCIIs to elicit the full T-cell response in an autonomous and peptide-specific fashion with consequences for adaptive immunity and immunotherapeutic approaches.

Differential Roles of Kinetic On- and Off-Rates in T-Cell Receptor Signal Integration Revealed with a Modified Fab’-DNA Ligand

“…Higher ligand on-rates have previously been observed in signaling hot spots (64), similar to the higher Fab’-DNA on-rate in LAT condensates that we observe here. The positive feedback model highlights how TCRs and pMHCs can rapidly transition from a purely random distribution (65, 66) to a clustered distribution with high signaling activity (55, 67, 68) when interacting with a high density of high-affinity ligand. In agreement with this experimentally observed behavior, LAT condensates were found to form faster in areas of higher local density of bound TCR in a recent computation model (69).…”

T-cell virtuosity in ‘‘knowing thyself”

“…A major obstacle to activation by pre-clustered p-MHC is that ab T cells comfortably respond to just a few p-MHC agonists dispersed among a huge excess of self p-MHC (79,80,113) and the probability of finding two or more rare p-MHC agonists associated at random in the same oligomer is vanishingly small. Also, crystal structures of p-MHC alone or complexed with TCRab are monomeric and accurate super-resolution imaging found no evidence for MHC-II clusters on agonist-loaded APC that otherwise stimulate T cells (114). Alternatively, p-MHC-TCR-CD3 pairs may laterally segregate and be drawn closer if receptor-ligand pairs of much longer size (e.g., ICAM-LAF-1) form nearby (115).…”