title: A model for antigen-induced T cell unresponsiveness based on autophosphorylative protein tyrosine kinase activity.
abstract: Helper T cell signaling is initiated by the aggregation of TCR with the induction of tyrosine kinase activity as one of the earliest consequences. Here, a theoretical model for antigen-induced unresponsiveness is presented that relies on a cascade of tyrosine phosphorylation-dephosphorylation cycles. A mechanism is described for both desensitization in the presence of antigen and persistent lowering of cell responsiveness after stimulus removal. An important component of the model, leading to bistability, is the presence of autophosphorylating protein tyrosine kinases in the early steps of TCR signaling. One of its predictions is that, following stimulation, the net phosphorylative activity of these receptor-associated tyrosine kinases will remain above background level after removal of the antigen. It is proposed that this residual tyrosine kinase activity is linked to a deficient signal transduction capacity of the TCR system that leads to a state of prolonged unresponsiveness. In addition, the present analysis defines the notion of a signaling threshold for hyporesponsiveness induction, associated with a durable switch and amplification of the net tyrosine kinase activity. This approach emphasizes the role of tyrosine kinases in the down-regulation of cellular competence.
authors.affiliation: Centre for Nonlinear Phenomena and Complex Systems, Université Libre de Bruxelles, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Kaufman
authors.forename: F
authors.initials: F
authors.lastname: Andris
authors.forename: O
authors.initials: O
authors.lastname: Leo
mesh_terms: D017951:Antigen Presentation; D015536:Down-Regulation; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D018448:Models, Immunological; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology* / Q000502:physiology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases