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

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.