Modeling and analysis of early events in T-lymphocyte antigen-activated intracellular-signaling pathways

Y. Zheng, V. Balakrishnan, G. Buzzard, R. Geahlen, M. Harrison and A. Rundell

Journal of Computational and Applied Mathematics, 184, 320-341, 2005

Abstract: The T-cell antigen-activated signaling pathway is a highly regulated intracellular biochemical system that is crucial for initiating an appropriate adaptive immune response.T o improve the understanding of the complex regulatory mechanisms controlling the early events inT-cell signaling, a detailed mathematical modelwas 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 signaling intermediate and indicated an initial rapid cascade of phosphorylation events followed by a comparatively slowsignal 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 Tcell 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.Moreo ver, 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.Quantitati ve analysis in this paper has helped identify potential regulatory mechanisms in the early T-cell signaling events.This integrated approach provides a framework to quantify and discover the ensemble of interconnected T-cell antigen-activated signaling pathways from limited experimental data.

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