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 is 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 observe pMHCIIs as monomeric, randomly distributed entities diffusing rapidly after entering the APC surface. Synaptic TCR engagement of highly abundant endogenous pMHCIIs is low or non‐existent and affects 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. image Quantitative single molecule live cell microscopy reveals pMHCIIs as monomeric, highly expressed, randomly distributed and predominantly fast diffusing entities on APC surfaces. Single agonist pMHCIIs sensitize T‐cells in an autonomous fashion. pMHCIIs appear randomly distributed at high densities on the surface of activated BMDCs and B‐cells. Synaptic TCR‐engagement of highly abundant endogenous pMHCIIs is low or non‐existent. Neither TCR‐engagement of rare agonist pMHCII in synapses nor agonist‐induced TCR‐proximal signaling is affected. Agonist pMHCIIs activate cognate T‐cells in an autonomous fashion. Rare antigens are best detected when spread homogeneously on APC surfaces.