4.8 Article

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

Journal

SCIENCE
Volume 372, Issue 6546, Pages 1056-+

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abe9124

Keywords

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Funding

  1. Australian Research Council (ARC) [DP170103631, DP201102776, CE140100011]
  2. National Health and Medical Research Council of Australia (NHMRC) [APP1182086, APP1155162]
  3. NSW Cancer Council [APP1128488]
  4. Singapore Ministry of Health's National Medical Research Council [CBRG/0097/2015]
  5. Singapore Ministry of Education [2014-T2-1136]
  6. ARC Future Fellowship
  7. NHMRC Senior Research Fellowship
  8. ARC Laureate Fellowship

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The study found that the T cell receptor recognizes peptide-major histocompatibility complexes with a highly conserved docking polarity, which affects T cell activation and recruitment in vivo. The canonical docking of TCR-pMHCI is essential for optimal T cell signaling.
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 TCRb-variable (TRBV) 17(+) TCRs from the naive mouse CD8(+) T cell repertoire that recognizes the H-2D(b)-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.

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