Frontiers in Immunology (Sep 2013)

Cellular-level versus receptor-level response threshold hierarchies in T-cell activation

  • Hugo Antonius van den Berg,
  • Kristin eLadell,
  • Kelly eMiners,
  • Bruno eLaugel,
  • Sian eLlewellyn-Lacey,
  • Mathew eClement,
  • David K Cole,
  • Emma eGostick,
  • Linda eWooldridge,
  • Andrew Kelvin Sewell,
  • John Stephen Bridgeman,
  • David A Price,
  • David A Price

DOI
https://doi.org/10.3389/fimmu.2013.00250
Journal volume & issue
Vol. 4

Abstract

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Peptide-MHC (pMHC) ligand engagement by T-cell receptors (TCRs) elicits a variety of cellular responses, some of which require substantially more TCR-mediated stimulation than others. This threshold hierarchy could reside at the receptor level, where different response pathways branch off at different stages of the TCR/CD3 triggering cascade, or at the cellular level, where the cumulative TCR signal registered by the T-cell is compared to different threshold values. Alternatively, dual-level thresholds could exist. In this study, we show that the cellular hypothesis provides the most parsimonious explanation consistent with the data. Further, we derive a mathematical model that describes how ligand density, affinity, and off-rate all affect signalling in distinct ways. However, under the kinetic regime prevailing in the experiments reported here, the TCR/pMHCI dissociation rate was found to be the main governing factor. The CD8 coreceptor modulated the TCR/pMHCI interaction and altered peptide ligand potency. Collectively, these findings elucidate the relationship between TCR/pMHCI kinetics and cellular function, thereby providing an integrated mechanistic understanding of T-cell response profiles.

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