Model of Paradoxical Signaling Regulated T-Cell Population Control for Design of Synthetic Circuits

摘要

Paradoxical signaling occurs when the same signaling molecule can trigger antagonistic cell functions. For example, T-Cells secret cytokine IL-2 which promotes T-Cell proliferation and also affects cell death. It has been shown that cells with this signaling capability have bi-stable population dynamics. Cells can achieve identical levels of population homeostasis for initial cell concentrations within the region of attraction. These capabilities are desirable in the context of synthetic population control circuits designed for application in therapeutic treatment of various diseases. It thus becomes important to understand the dependence of the cell system on the intracellular paradoxical components and to develop accurate models to provide insight into optimal design characteristics. Here, we create a model that integrates three IL-2 driven intracellular mechanisms that trigger 1) T-cell proliferation 2) T-cell apoptosis and 3) IL-2 production. Using this model, we are able to explore the internal mechanisms necessary for paradoxical signaling in T-Cells. It was shown that the intracellular mechanisms considered were sufficient to produce population dynamic characteristics of paradoxical signaling consistent with published systems level models and data. Furthermore, analysis of parameters revealed dependency of population bistability on the production and activation of the specific intracellular proteins considered.