Zareie Pirooz, Szeto Christopher, Farenc Carine, Gunasinghe Sachith D, Kolawole Elizabeth M, Nguyen Angela, Blyth Chantelle, Sng Xavier Y X, Li Jasmine, Jones Claerwen M, Fulcher Alex J, Jacobs Jesica R, Wei Qianru, Wojciech Lukasz, Petersen Jan, Gascoigne Nicholas R J, Evavold Brian D, Gaus Katharina, Gras Stephanie, Rossjohn Jamie, La Gruta Nicole L
Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
European Molecular Biology Laboratory (EMBL) Australia Node in Single Molecule Science and the ARC Centre of Excellence in Advanced Molecular Imaging, School of Medical Sciences, University of New South Wales, New South Wales, Australia.
Science. 2021 Jun 4;372(6546). doi: 10.1126/science.abe9124.
T cell receptor (TCR) recognition of peptide-major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using "reversed-docking" TCRβ-variable (TRBV) 17 TCRs from the naïve mouse CD8 T cell repertoire that recognizes the H-2D-NP epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR-pMHCI binding or clustering characteristics. Canonical TCR-pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR-pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR-pMHC docking topology is mandated by T cell signaling constraints.
T细胞受体（TCR）对肽-主要组织相容性复合体（pMHC）的识别具有高度保守的对接极性。这种极性是由识别还是信号传导限制驱动仍不清楚。使用来自识别H-2D-NP表位的幼稚小鼠CD8 T细胞库的“反向对接”TCRβ可变区（TRBV）17 TCR，我们证明它们无法支持T细胞活化和体内募集是反向对接极性的直接后果，而不是TCR-pMHCI结合或聚集特性。经典的TCR-pMHCI对接将CD8/Lck最佳地定位到CD3复合体，而反向的TCR-pMHCI极性则阻止了这一点。通过使Lck与CD8解离，规避了对经典对接的要求。因此，T细胞信号传导限制决定了TCR-pMHC对接拓扑结构的一致性。
