IL-2 sensitivity and exogenous IL-2 concentration gradient tune the productive contact duration of CD8(+) T cell-APC: a multiscale modeling study

Authored by Xuefeng Gao, Christophe Arpin, Jacqueline Marvel, Sotiris A Prokopiou, Olivier Gandrillon, Fabien Crauste

Date Published: 2016

DOI: 10.1186/s12918-016-0323-y

Sponsors: ANR grant PrediVac Finovi Fondation Rhône-Alpes Complex Systems Institute Université Claude Bernard Lyon 1 Fonds Europeen de Developpement Regional Institut National de la Sante Et de la Recherche Medicale

Platforms: Python

Model Documentation: Other Narrative Flow charts Mathematical description

Model Code URLs: https://ndownloader.figshare.com/files/7205315

Abstract

The CD8(+) T cell immune response fights acute infections by intracellular pathogens and, by generating an immune memory, enables immune responses against secondary infections. Activation of the CD8(+) T cell immune response involves a succession of molecular events leading to modifications of CD8(+) T cell population. To understand the endogenous and exogenous mechanisms controlling the activation of CD8(+) T cells and to investigate the influence of early molecular events on the long-term cell population behavior, we developed a multiscale computational model. It integrates three levels of description: a Cellular Potts model describing the individual behavior of CD8(+) T cells, a system of ordinary differential equations describing a decision-making molecular regulatory network at the intracellular level, and a partial differential equation describing the diffusion of IL-2 in the extracellular environment. Results: We first calibrated the model parameters based on in vivo data and showed the model's ability to reproduce early dynamics of CD8(+) T cells in murine lymph nodes after influenza infection, both at the cell population and intracellular levels. We then showed the model's ability to reproduce the proliferative responses of CD5(hi) and CD5(lo) CD8(+) T cells to exogenous IL-2 under a weak TCR stimulation. This stressed the role of shortlasting molecular events and the relevance of explicitly describing both intracellular and cellular scale dynamics. Our results suggest that the productive contact duration of CD8(+) T cell-APC is influenced by the sensitivity of individual CD8(+) T cells to the activation signal and by the IL-2 concentration in the extracellular environment. Conclusions: The multiscale nature of our model allows the reproduction and explanation of some acquired characteristics and functions of CD8(+) T cells, and of their responses to multiple stimulation conditions, that would not be accessible in a classical description of cell population dynamics that would not consider intracellular dynamics.

Tags

Agent-based model activation Memory Dendritic cells Effector In-vivo Gene-expression Lymph-nodes Adaptive immunity Bet