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

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.Author summary: CD4+ T cells are a key part of the adaptive immune system. They differentiate into different phenotypes to carry out different functions. They do so by secreting molecules called cytokines to regulate other immune cells. Multi-scale modeling can potentially explain their emergent behaviors by integrating biological phenomena occurring at different spatial (intracellular, cellular, and systemic), temporal, and organizational scales (signal transduction, gene regulation, metabolism, cellular behaviors, and cytokine transport). We built a computational platform by combining disparate modeling frameworks (compartmental ordinary differential equations, agent-based modeling, Boolean network modeling, and constraint-based modeling). We validated the platform’s ability to predict CD4+ T cells’ emergent behaviors by reproducing their differentiation patterns, metabolic regulation, and population dynamics in response to influenza infection. We then used it to predict and explain novel switch-like and oscillatory behaviors for CD4+ T cells. On the basis of these results, we believe that our multi-approach and multi-scale platform will be a valuable addition to the systems immunology toolkit. In addition to its immediate relevance to CD4+ T cells, it also has the potential to become the foundation of a virtual immune system.