title: Cellular-level versus receptor-level response threshold hierarchies in T-cell activation.
abstract: 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 data obtained from an in-depth analysis of distinct functional responses elicited in a clonal T-cell system by a spectrum of biophysically defined altered peptide ligands across a range of concentrations. Further, we derive a mathematical model that describes how ligand density, affinity, and off-rate all affect signaling in distinct ways. However, under the kinetic regime prevailing in the experiments reported here, the TCR/pMHC class I (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.
authors.affiliation: University of Warwick , Coventry , UK.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Kelly
authors.initials: K
authors.lastname: Miners
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.forename: Sian
authors.initials: S
authors.lastname: Llewellyn-Lacey
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: John S
authors.initials: JS
authors.lastname: Bridgeman
authors.forename: David A
authors.initials: DA
authors.lastname: Price
keywords: T-cell activation; T-cell cross-reactivity; T-cell receptor
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