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Modeling and analysis of early events in T-lymphocyte antigen-activated intracellular-signalling pathways. (English) Zbl 1073.92012

Summary: The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical system that is crucial for initiating an appropriate adaptive immune response. To improve the understanding of the complex regulatory mechanisms controlling the early events in T-cell signalling, a detailed mathematical model was developed that utilizes ordinary differential equations to describe chemical reactions of the signaling pathway. The model parameter values were constrained by experimental data on the activation of a specific signalling intermediate and indicated an initial rapid cascade of phosphorylation events followed by a comparatively slow signal downregulation. Nonlinear analysis of the model suggested that thresholding and bistability occur as a result of the embedded positive and negative feedback loops within the model.
These nonlinear system properties may enhance the T-cell receptor specificity and provide sub-threshold noise filtering with switch-like behavior to ensure proper cell response. Additional analysis using a reduced second-order model led to further understanding of the observed system behavior. Moreover, the interactions between the positive and negative feedback loops enabled the model to exhibit, among a variety of other feasible dynamics, a sustained oscillation that corresponds to a stable limit cycle in the two-dimensional phase plane. Quantitative analysis in this paper has helped identify potential regulatory mechanisms in the early T-cell signalling events. This integrated approach provides a framework to quantify and discover the ensemble of interconnected T-cell antigen-activated signalling pathways from limited experimental data.

MSC:

92C40 Biochemistry, molecular biology
37N25 Dynamical systems in biology
92C55 Biomedical imaging and signal processing

Software:

AUTO; HomCont
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References:

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