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

Abstract

Background: 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 CD5hi and CD5lo CD8+ T cells to exogenous IL-2 under a weak TCR stimulation. This stressed the role of short-lasting 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.