Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

Processes

Jeffrey P. Perley³  Judith Mikolajczak²  Gregery T. Buzzard¹  Marietta L. Harrison²  Ann E. Rundell³ 

[1]Department of Mathematics, Purdue University, 150 N. University St., West Lafayette, IN 47907, USA

[2] E-Mail:

[3]Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Dr., West Lafayette, IN 47906, USA

[4] E-Mails:

[5]Weldon School of Biomedical Engineering, Purdue University, 206 S. Martin Jischke Dr., West Lafayette, IN 47907, USA

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关键词: T-cell activation;    CD28 costimulation;    calcium;    Erk;    NFκB;    mTOR;    CD45;    SHP1;    mathematical model;   

DOI  :  10.3390/pr2040867

来源: mdpi

【 摘 要 】

Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR) and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKCθ and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and IκBα signaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1) SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2) CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3) elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs), is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.