Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose
T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systema...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
National Academy of Sciences
2016
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| _version_ | 1826278915783524352 |
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| author | Lever, M Lim, H Kruger, P Nguyen, J Trendel, N Abu-Shah, E Maini, P van der Merwe, P Dushek, O |
| author_facet | Lever, M Lim, H Kruger, P Nguyen, J Trendel, N Abu-Shah, E Maini, P van der Merwe, P Dushek, O |
| author_sort | Lever, M |
| collection | OXFORD |
| description | T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. |
| first_indexed | 2024-03-06T23:51:04Z |
| format | Journal article |
| id | oxford-uuid:729d5f39-1e9b-4a73-8b7a-27cf81faed25 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:51:04Z |
| publishDate | 2016 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:729d5f39-1e9b-4a73-8b7a-27cf81faed252022-03-26T19:51:20ZArchitecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and doseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:729d5f39-1e9b-4a73-8b7a-27cf81faed25EnglishSymplectic Elements at OxfordNational Academy of Sciences2016Lever, MLim, HKruger, PNguyen, JTrendel, NAbu-Shah, EMaini, Pvan der Merwe, PDushek, OT cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. |
| spellingShingle | Lever, M Lim, H Kruger, P Nguyen, J Trendel, N Abu-Shah, E Maini, P van der Merwe, P Dushek, O Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title | Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title_full | Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title_fullStr | Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title_full_unstemmed | Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title_short | Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose |
| title_sort | architecture of a minimal signaling pathway explains the t cell response to a 1 million fold variation in antigen affinity and dose |
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