A cell topography-based mechanism for ligand discrimination by the T cell receptor

Research output: Contribution to journalArticle

Abstract

The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.

Details

Authors
  • Ricardo A. Fernandes
  • Kristina A. Ganzinger
  • Justin C. Tzou
  • Peter Jönsson
  • Steven F. Lee
  • Matthieu Palayret
  • Ana Mafalda Santos
  • Alexander R. Carr
  • Aleks Ponjavic
  • Veronica T. Chang
  • Charlotte Macleod
  • B. Christoffer Lagerholm
  • Alan E. Lindsay
  • Omer Dushek
  • Andreas Tilevik
  • Simon J. Davis
  • David Klenerman
External organisations
  • University of Cambridge
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Physical Chemistry
Original languageEnglish
Pages (from-to)14002-14010
JournalProceedings of the National Academy of Sciences
Volume116
Issue number28
Publication statusPublished - 2019 May 22
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes