A model for antigen-induced T cell unresponsiveness based on autophosphorylative protein tyrosine kinase activity |
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Authors: | Kaufman, Marcelle Andris, Fabienne Leo, Oberdan |
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Affiliation: | Centre for Nonlinear Phenomena and Complex Systems, Université Libre de Bruxelles Campus Plaine CP 231, 1050 Bruxelles, Belgium 1 Laboratoire de Physiologie Animale, Université Libre de Bruxelles CP 300, 67, rue des Chevaux, 1640 Rhode St Genèse, Belgium |
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Abstract: | Helper T cell signaling is initiated by the aggregation of TCRwith the induction of tyrosine kinase activity as one of theearliest consequences. Here, a theoretical model for antigen-inducedunresponsiveness is presented that relies on a cascade of tyrosinephosphorylation- dephoshorylation cycles. A mechanism is describedfor both desensitization in the presence of antigen and persistentlowering of cell responsiveness after stimulus removal. An importantcomponent of the model, leading to bistability, is the presenceof autophosphorylating protein tyrosine kinases in the earlysteps of TCR signaling. One of its predictions is that, followingstimulation, the net phosphorylative activity of these receptor-associatedtyrosine kinases will remain above background level after removalof the antigen. It is proposed that this residual tyrosine kinaseactivity is linked to a deficient signal transduction capacityof the TCR system that leads to a state of prolonged unresponsiveness.In addition, the present analysis defines the notion of a signalingthreshold for hyporesponsiveness induction, associated witha durable switch and amplification of the net tyrosine kinaseactivity. This approach emphasizes the role of tyrosine kinasesin the down-regulation of cellular competence. |
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Keywords: | anergy bistability long-term memory receptor desensitization signal transduction T cell activation |
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