Canonical T cell receptor docking on peptide-MHC is essential for T cell signaling.
Pirooz ZareieChristopher SzetoCarine FarencSachith D GunasingheElizabeth Motunrayo KolawoleAngela NguyenChantelle BlythXavier Y X SngJasmine LiClaerwen M JonesAlex J FulcherJesica R JacobsQianru WeiLukasz WojciechJan PetersenNicholas R J GascoigneBrian D EvavoldKatharina GausStephanie GrasJamie RossjohnNicole L La GrutaPublished in: Science (New York, N.Y.) (2021)
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-2Db-NP366 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.