Cellular-level versus receptor-level response threshold hierarchies in T-cell activation
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 differe...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-09-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00250/full |
| _version_ | 1818007603575259136 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hugo Antonius van den Berg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T05:17:48Z |
| format | Article |
| id | doaj.art-c3570d2cea314a2187180619c9cbec4f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T05:17:48Z |
| publishDate | 2013-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c3570d2cea314a2187180619c9cbec4f2022-12-22T02:10:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242013-09-01410.3389/fimmu.2013.0025056678Cellular-level versus receptor-level response threshold hierarchies in T-cell activationHugo Antonius van den Berg0Kristin eLadell1Kelly eMiners2Bruno eLaugel3Sian eLlewellyn-Lacey4Mathew eClement5David K Cole6Emma eGostick7Linda eWooldridge8Andrew Kelvin Sewell9John Stephen Bridgeman10David A Price11David A Price12Warwick UniversityUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffUniversity of CardiffNational Institutes of HealthPeptide-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.http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00250/fullKineticsT-cell receptorpeptide ligandsT-cell cross-reactivityT-cell activation |
| spellingShingle | 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 Cellular-level versus receptor-level response threshold hierarchies in T-cell activation Frontiers in Immunology Kinetics T-cell receptor peptide ligands T-cell cross-reactivity T-cell activation |
| title | Cellular-level versus receptor-level response threshold hierarchies in T-cell activation |
| title_full | Cellular-level versus receptor-level response threshold hierarchies in T-cell activation |
| title_fullStr | Cellular-level versus receptor-level response threshold hierarchies in T-cell activation |
| title_full_unstemmed | Cellular-level versus receptor-level response threshold hierarchies in T-cell activation |
| title_short | Cellular-level versus receptor-level response threshold hierarchies in T-cell activation |
| title_sort | cellular level versus receptor level response threshold hierarchies in t cell activation |
| topic | Kinetics T-cell receptor peptide ligands T-cell cross-reactivity T-cell activation |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00250/full |
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