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Cellular-level versus receptor-level response threshold hierarchies in T-Cell activation
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Berg, Hugo van den , Ladell, Kristin, Miners, Kelly, Laugel, Bruno, Llewellyn-Lacey, Sian, Clement, Mathew, Cole, David K., Gostick, Emma, Wooldridge, L., Sewell, Andrew K., Bridgeman, John S. and Price, D. A. (2013) Cellular-level versus receptor-level response threshold hierarchies in T-Cell activation. Frontiers in Immunology, Volume 4 . Article number 200. doi:10.3389/fimmu.2013.00250 ISSN 1664-3224.
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WRAP_VanBerg_fimmu-04-00250.pdf - Published Version Available under License Creative Commons Attribution. Download (4063Kb) | Preview |
Official URL: http://dx.doi.org/10.3389/fimmu.2013.00250
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.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QH Natural history > QH301 Biology | ||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Mathematics |
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Library of Congress Subject Headings (LCSH): | T cells -- Receptors , Cell receptors, T cells, Cytology -- Research | ||||
Journal or Publication Title: | Frontiers in Immunology | ||||
Publisher: | Frontiers Research Foundation | ||||
ISSN: | 1664-3224 | ||||
Official Date: | 5 September 2013 | ||||
Dates: |
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Volume: | Volume 4 | ||||
Page Range: | Article number 200 | ||||
DOI: | 10.3389/fimmu.2013.00250 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Open Access (Creative Commons) | ||||
Date of first compliant deposit: | 25 December 2015 | ||||
Date of first compliant Open Access: | 25 December 2015 | ||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC) | ||||
Grant number: | BB/H001085/1 (BBSRC) |
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