A multi-approach and multi-scale platform to model CD4+ T cells responding to infections.

Kenneth Y Wertheim,Tomáš Helikar,Ab Rauf Shah,Alyssa La Fleur,Bhanwar Lal Puniya,Matteo Barberis,Kathryn Miller-Jensen

doi:10.1371/journal.pcbi.1009209

Abstract

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.

Highlights

Immune responses mediated by CD4+ T cells involve complex interactions among immune cells and molecules
CD4+ T cells are a key part of the adaptive immune system
To fully understand these complex interactions underlying the dynamics of CD4+ T cell immune response, we must integrate events taking place at various spatial, temporal, and organizational scales, such as immune cell proliferation, development, and migration; cell-cell and cell-molecule interactions; intracellular signaling; and intracellular metabolism

Summary

Introduction

Immune responses mediated by CD4+ T cells involve complex interactions among immune cells and molecules. Activated CD4+ T cells utilize certain signaling and metabolic pathways, such as aerobic glycolysis, to produce the energy and molecular precursors required to achieve a specific mixture of phenotypes [1,4]. To fully understand these complex interactions underlying the dynamics of CD4+ T cell immune response, we must integrate events taking place at various spatial, temporal, and organizational scales, such as immune cell proliferation, development, and migration; cell-cell and cell-molecule interactions; intracellular signaling; and intracellular metabolism.

Methods

Results

Conclusion