Feedback control of T–cell receptor activation

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Abstract
The specificity and sensitivity of T–cell recognition is vital to the immune response. Ligand engagement with the T–cell receptor (TCR) results in the activation of a complex sequence of signalling events, both on the cell membrane and intracellularly. Feedback is an integral part of these signalling pathways, yet is often ignored in standard accounts of T–cell signalling. Here we show, using a mathematical model, that these feedback loops can explain the ability of the TCR to discriminate between ligands with high specificity and sensitivity, as well as provide a mechanism for sustained signalling. The model also explains the recent counter–intuitive observation that endogenous ‘null’ ligands can significantly enhance T–cell signalling. Finally, the model may provide an archetype for receptor switching based on kinase–phosphatase switches, and thus be of interest to the wider signalling community.