Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Significance T cells initiate and regulate adaptive immune responses when their T-cell antigen receptors recognize antigens. The T-cell response is known to depend on the antigen affinity/dose, but the precise relationship, and the mechanisms underlying it, are debated. To resolve the debate, we stimulated T cells with antigens spanning a 1 million-fold range in affinity/dose. We found that a different antigen (and hence different affinity) produced the largest T-cell response at different doses. Using model identification algorithms, we report a simple mechanistic model that can predict the T-cell response from the physiological low-affinity regime into the high-affinity regime applicable to therapeutic receptors. 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.