Abstract

T cells initiate adaptive immune responses when their T cell antigen receptors (TCRs) recognise antigenic peptides bound to major histocompatibility complexes (pMHC). The binding of pMHC ligands to the TCR can trigger a large signal transduction cascade leading to T cell activation, as measured by the secretion effector cytokines/chemokines. Although the signalling proteins involved have been identified, it is still not understood how the cellular signalling network that they form converts the dose and affinity of pMHC into T cell activation. Here we use a holistic method to infer the signalling architecture from T cell activation data generated by stimulating T cells with a 100,000-fold variation in pMHC affinity/dose. We observe bell-shape dose-response curves and a different optimal pMHC affinity at different pMHC doses. We show that this can be explained by a unique, tractable, and modular phenotypic model of signalling that includes kinetic proofreading with limited sign alling coupled to incoherent feedforward but not negative feedback. The work provides a complementary approach for studying cellular signalling that does not require full details of biochemical pathways.

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