title: Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.
abstract: 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.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lever
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kruger
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Nguyen
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Trendel
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Enas
authors.initials: E
authors.lastname: Abu-Shah
authors.affiliation: Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford OX2 6GG, United Kingdom.
authors.forename: Philip Kumar
authors.initials: PK
authors.lastname: Maini
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
authors.forename: Philip Anton
authors.initials: PA
authors.lastname: van der Merwe
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom; Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford OX2 6GG, United Kingdom omer.dushek@path.ox.ac.uk.
authors.forename: Omer
authors.identifier: 0000-0001-5847-5226
authors.initials: O
authors.lastname: Dushek
mesh_terms: D020126:Brefeldin A / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D018448:Models, Immunological; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D020126:Brefeldin A; D007371:Interferon-gamma
keywords: T-cell receptor; immunology; pathway architecture; signaling; systems biology