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

HA van den Berg, K Ladell, S Llewellyn-Lacey… - Frontiers in …, 2013 - frontiersin.org
HA van den Berg, K Ladell, S Llewellyn-Lacey, M Clement, AK Sewell, JS Bridgeman
Frontiers in immunology, 2013frontiersin.org
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 …
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.
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