Feedback control of T-cell receptor activation.
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.
Chan
Cliburn
C
Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
Stark
Jaroslav
J
George
Andrew J T
AJ
D000818:Animals; D025461:Feedback, Physiological / Q000276:immunology*; D008024:Ligands; D018448:Models, Immunological; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000276:immunology*; D013269:Stochastic Processes
D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases