A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface.Here,we used in situ fluorescence resonance energy transfer(FRET)to measure the distances of single...A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface.Here,we used in situ fluorescence resonance energy transfer(FRET)to measure the distances of single TCR–pMHC bonds and the conformations of individual TCR–CD3ζreceptors at the membranes of live primary T cells.We found that a TCR discriminates between closely related peptides by forming single TCR–pMHC bonds with different conformations,and the most potent pMHC forms the shortest bond.The bond conformation is an intrinsic property that is independent of the binding affinity and kinetics,TCR microcluster formation,and CD4 binding.The bond conformation dictates the degree of CD3ζdissociation from the inner leaflet of the plasma membrane via a positive calcium signaling feedback loop to precisely control the accessibility of CD3ζITAMs for phosphorylation.Our data revealed the mechanism by which a TCR deciphers the structural differences among peptides via the TCR–pMHC bond conformation.展开更多
基金This work was mainly supported by NIH grants R00AI106941 and R21AI120010NSF CAREER Award 1653782,a Chicago Biomedical Consortium Catalyst Award(to J.H.)+1 种基金postdoctoral grant PDR-092(to D.K.S.),with additional support from the Searle Funds at The Chicago Community TrustThis work is also supported by NIH grant R01AI126756(to E.J.A.)and R01CA022677(to H.S.).
文摘A major unanswered question is how a TCR discriminates between foreign and self-peptides presented on the APC surface.Here,we used in situ fluorescence resonance energy transfer(FRET)to measure the distances of single TCR–pMHC bonds and the conformations of individual TCR–CD3ζreceptors at the membranes of live primary T cells.We found that a TCR discriminates between closely related peptides by forming single TCR–pMHC bonds with different conformations,and the most potent pMHC forms the shortest bond.The bond conformation is an intrinsic property that is independent of the binding affinity and kinetics,TCR microcluster formation,and CD4 binding.The bond conformation dictates the degree of CD3ζdissociation from the inner leaflet of the plasma membrane via a positive calcium signaling feedback loop to precisely control the accessibility of CD3ζITAMs for phosphorylation.Our data revealed the mechanism by which a TCR deciphers the structural differences among peptides via the TCR–pMHC bond conformation.
