Section: Research Program

Multi-scale modeling of the immune response

The main objective of this part is to develop models that make it possible to investigate the dynamics of the adaptive CD8 T cell immune response, and in particular to focus on the consequences of early molecular events on the cellular dynamics few days or weeks later: this would help developing predictive tools of the immune response in order to facilitate vaccine development and reduce costs. This work requires a close and intensive collaboration with immunologist partners.

We recently published a model of the CD8 T cell immune response characterizing differentiation stages, identified by biomarkers, able to predict the quantity of memory cells from early measurements ( [40]). In parallel, we improved our multiscale model of the CD8 T cell immune response, by implementing a full differentiation scheme, from naïve to memory cells, based on a limited set of genes and transcription factors.

Our first task will be to infer an appropriate gene regulatory network (GRN) using single cell data analysis (generate transcriptomics data of the CD8 T cell response to diverse pathogens), the previous biomarkers we identified and associated to differentiation stages, as well as piecewise-deterministic Markov processes (Ulysse Herbach's PhD thesis, ongoing).

Our second task will be to update our multiscale model by first implementing the new differentiation scheme we identified ( [40]), and second by embedding CD8 T cells with the GRN obtained in our first task (see above). This will lead to a multi-scale model incorporating description of the CD8 T cell immune response both at the molecular and the cellular levels (Simon Girel's PhD thesis, ongoing).

In order to further develop our multiscale model, we will consider an agent-based approach for the description of the cellular dynamics. Yet, such models, coupled to continuous models describing GRN dynamics, are computationally expensive, so we will focus on alternative strategies, in particular on descriptions of the cellular dynamics through both continuous and discrete models, efficiently coupled. Using discrete models for low cell numbers and continuous (partial differential equations) models for large cell numbers, with appropriate coupling strategies, can lead to faster numerical simulations, and consequently can allow performing intense parameter estimation procedures that are necessary to validate models by confronting them to experimental data, both at the molecular and cellular scales.

The final objective will be to capture CD8 T cell responses in different immunization contexts (different pathogens, tumor) and to predict cellular outcomes from molecular events.