TY - JOUR
T1 - A multi-approach and multi-scale platform to model CD4+ T cells responding to infections
AU - Wertheim, Kenneth Y.
AU - Puniy, Bhanwar Lal
AU - Alyssa La Fleur, I.
AU - Shah, Ab Rauf
AU - Barberis, Matteo
AU - Helikar, Tomáš
N1 - Funding Information:
This work was supported by NIH grant 1R35GM119770 to T.H. and by the Systems Biology Grant of the University of Surrey to M.B. National Institutes of Health (NIH) https://www.nih. gov/ University of Surrey https://www.Surrey.ac.uk/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright: © 2021 Wertheim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2021/8
Y1 - 2021/8
N2 - Immune responses rely on a complex adaptive system in which the body and infections interact at multiple scales and in different compartments. We developed a modular model of CD4+ T cells, which uses four modeling approaches to integrate processes at three spatial scales in different tissues. In each cell, signal transduction and gene regulation are described by a logical model, metabolism by constraint-based models. Cell population dynamics are described by an agent-based model and systemic cytokine concentrations by ordinary differential equations. A Monte Carlo simulation algorithm allows information to flow efficiently between the four modules by separating the time scales. Such modularity improves computational performance and versatility and facilitates data integration. We validated our technology by reproducing known experimental results, including differentiation patterns of CD4+ T cells triggered by different combinations of cytokines, metabolic regulation by IL2 in these cells, and their response to influenza infection. In doing so, we added multi-scale insights to single-scale studies and demonstrated its predictive power by discovering switch-like and oscillatory behaviors of CD4+ T cells that arise from nonlinear dynamics interwoven across three scales. We identified the inflamed lymph node's ability to retain naive CD4+ T cells as a key mechanism in generating these emergent behaviors. We envision our model and the generic framework encompassing it to serve as a tool for understanding cellular and molecular immunological problems through the lens of systems immunology.
AB - Immune responses rely on a complex adaptive system in which the body and infections interact at multiple scales and in different compartments. We developed a modular model of CD4+ T cells, which uses four modeling approaches to integrate processes at three spatial scales in different tissues. In each cell, signal transduction and gene regulation are described by a logical model, metabolism by constraint-based models. Cell population dynamics are described by an agent-based model and systemic cytokine concentrations by ordinary differential equations. A Monte Carlo simulation algorithm allows information to flow efficiently between the four modules by separating the time scales. Such modularity improves computational performance and versatility and facilitates data integration. We validated our technology by reproducing known experimental results, including differentiation patterns of CD4+ T cells triggered by different combinations of cytokines, metabolic regulation by IL2 in these cells, and their response to influenza infection. In doing so, we added multi-scale insights to single-scale studies and demonstrated its predictive power by discovering switch-like and oscillatory behaviors of CD4+ T cells that arise from nonlinear dynamics interwoven across three scales. We identified the inflamed lymph node's ability to retain naive CD4+ T cells as a key mechanism in generating these emergent behaviors. We envision our model and the generic framework encompassing it to serve as a tool for understanding cellular and molecular immunological problems through the lens of systems immunology.
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U2 - 10.1371/journal.pcbi.1009209
DO - 10.1371/journal.pcbi.1009209
M3 - Article
C2 - 34343169
AN - SCOPUS:85112248857
SN - 1553-734X
VL - 17
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 8
M1 - e1009209
ER -