Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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