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

Abstract

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 Processes 2014, 2 868 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.

Mathematical Models for Immunology: Current State of the Art and Future Research Directions

“…Other types of model that have been beneficial to immunology research, despite a lack of model calibration in the absence of relevant data, are the complex systems immunology models that attempt to simulate very large cell signalling pathways (Perley et al. 2014 ), or models describing complex nonlinear interactions between large numbers of immune cells, cytokines and chemokines (Bianca et al. 2012 ; Pappalardo et al.…”

“… 2008 ), or in the context of the adaptive immune responses (Perley et al. 2014 ). Since most of the B cell and T cell receptors discussed previously can initiate intracellular signalling by the activation of protein tyrosine kinases (Murphy 2012 ), some of these models also investigate signalling through T cell receptors (Perley et al.…”

“…Since most of the B cell and T cell receptors discussed previously can initiate intracellular signalling by the activation of protein tyrosine kinases (Murphy 2012 ), some of these models also investigate signalling through T cell receptors (Perley et al. 2014 ). In regard to innate immunity, one of the most investigated signalling pathway is the NF- B, which controls the regulation of genes involved in immune and inflammatory responses (Bonizzi and Karin 2004 ).…”

A Computational Study of the Effects of Syk Activity on B Cell Receptor Signaling Dynamics

“…Due to similarities in the signaling network, much of the model structure for the medial and downstream pathways required little modification. In particular, the model structure and equations for the MAPK pathway, which contains Erk, and the NF- κ B pathway, are analogous to those found in [ 16 ]. A diagram focusing on the signaling dynamics for our system is shown in Figure 1 .…”

“…Described in [ 3 , 16 ] are the remaining equations not shown here, i.e. , equations for Erkp, I κ B and NF- κ B, which are referenced below.…”