Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Abstract

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.

Catch bond models may explain how force amplifies TCR signaling and antigen discrimination

“…In addition, we fitted our model to two datasets published by other labs: 1) soluble mouse N15 TCRαβ interacted with VSV and two MT peptides bound to H2-K b (Supplementary Fig. 1e) 6 and 2) four mouse TCRs expressed on hybridomas interacted with NP 366 bound to the D227K mutant of H-2D b to prevent CD8 binding 15 (Supplementary Fig. 1f).…”

“…A recent study showed surprising features of reversed-polarity TRBV TCRs such that interactions of NP 366 :H-2D bD227K to TCRs B13.C1 and B17.C1 induced T cell signaling, whereas interactions of the same pMHC to B17.R1 and B17.R2 TCRs did not 15 . Despite that the former two TCRs formed catch-slip bonds with NP 366 :H-2D bD227K and the latter two TCRs formed slip-only bonds, the authors suggested that the signaling capability of the B13.C1 and B17.C1 TCRs could not be attributed to their force-prolonged bond lifetimes because the B17.C1 TCR-H-2D bD227K bond was shorter-lived than the B17.R2 TCR-NP 366 :H-2D bD227K bond across the entire force range tested.…”

“…All data are included in the article and Supplementary Materials. Previously published bond lifetime data were re-analyzed for models fitting 41–6,8,13,15,32,39 .…”

“…However, the relevance of this force range to T cell signaling remains incompletely understood. More perplexingly, some signal-inducing pMHC ligands form catch-slip bonds with TCRs but exhibit shorter lifetime than other pMHC ligands that do not induce signaling by, and form slip-only bonds with, the same TCRs even in the optimal force range 15 . These observations prompt the questions of what mechanism underlies the association of TCR–pMHC bond type with the T cell signaling capacity and what impact this specific force range has on TCR mechanotransduction.…”

The ITPRIPL1- CD3ε axis: a novel immune checkpoint controlling T cells activation

“…Still, immune evasion frequently happens [19, 20]. In the classic two-signal model of T-cell activation, the primary signal (signal one) is triggered by the ligation of the peptide-MHC to the TCR-CD3 complex, where the TCR represents the only receptor involved [21, 22]. Signal two is generated by the transduction of co-activators or co-inhibitors in the immune synapse following a calcium influx [23, 24].…”