TCR–pMHC bond conformation controls TCR ligand discrimination  

作　　者：Dibyendu KSasmal Wei Feng Sobhan Roy Peter Leung Yanran He Chufan Cai Guoshuai Cao Huada Lian Jian Qin Enfu Hui Hans Schreiber Erin JAdams Jun Huang 

机构地区：[1]The Pritzker School of Molecular Engineering,The University of Chicago,Chicago,IL,USA [2]Department of Biochemistry and Molecular Biology,The University of Chicago,Chicago,IL,USA [3]Department of Pathology,The University of Chicago,Chicago,IL,USA [4]Department of Materials Science&Engineering,Stanford University,Stanford,CA,USA [5]Department of Chemical Engineering,Stanford University,Stanford,CA,USA [6]Section of Cell&Developmental Biology,Division of Biological Sciences,University of California,San Diego,CA,USA

出　　处：《Cellular & Molecular Immunology》2020年第3期203-217,共15页中国免疫学杂志（英文版）

基　　金：This work was mainly supported by NIH grants R00AI106941 and R21AI120010;NSF CAREER Award 1653782,a Chicago Biomedical Consortium Catalyst Award(to J.H.);postdoctoral grant PDR-092(to D.K.S.),with additional support from the Searle Funds at The Chicago Community Trust;This work is also supported by NIH grant R01AI126756(to E.J.A.)and R01CA022677(to H.S.).

摘　　要：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.

关 键 词：Bond conformation T cell receptor Single molecule FRET ligand discrimination 

分 类 号：R392[医药卫生—免疫学]