biostudies-literatureLever MMedical Research CouncilRoyal SocietyWellcome TrustEngineering and Physical Sciences Research CouncilE6630-E6638https://www.ebi.ac.uk/biostudies/studies/S-EPMC5087047biostudies-literatureUnknown113(43)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 corrProceedings of the National Academy of Sciences of the United States of AmericaArchitecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.PMC50870471512113MR/J002011/1G9722488098363101799/Z/13/ZG19/31101799100262/Z/12/ZLim HSDushek OLever MKruger PTrendel Nvan der Merwe PAAbu-Shah EMaini PKNguyen JfalseArchitecture 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 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 corr2016-01-01T00:00:00Z2016 Oct2025-04-22T08:56:49.34Z2019-03-27T02:27:52ZS-EPMC50870472770290010.1073/pnas.1608820113