Monomeric agonist peptide/MHCII complexes activate T-cells in an autonomous fashion
René Platzer, Joschka Hellmeier, Janett Göhring, Iago Doel Perez, Philipp Schatzlmaier, Clara Bodner, Gerhard J. Schütz, Eva Sevcsik, Hannes Stockinger, Mario Brameshuber, Johannes B. Huppa
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.