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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.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





E6630 - E6638


T-cell receptor, immunology, pathway architecture, signaling, systems biology, Brefeldin A, Dose-Response Relationship, Immunologic, Gene Expression Regulation, HLA-A2 Antigen, Humans, Interferon-gamma, Interleukin-2, Jurkat Cells, Kinetics, Lymphocyte Activation, Models, Immunological, Phosphorylation, Primary Cell Culture, Protein Binding, Receptors, Antigen, T-Cell, Recombinant Proteins, Signal Transduction, T-Lymphocytes, beta 2-Microglobulin