CE45 - Mathématique, informatique, automatique, traitement du signal pour répondre aux défis de la biologie et de la santé

MultiscaleE Modeling Of CD8 T cell Immune REsponses – MEMOIRE

Submission summary

The aim of this project is to identify, at the single cell level, signatures associated with functionally relevant memory cell subsets, to characterize dynamical molecular networks that are predictive of their generation, and to build a multi-scale computational model of this process.
Following an acute intracellular-pathogen infection, memory CD8 T cells are generated. We now know that they differ from their naive ancestors by an increased responsiveness following antigen stimulation that results from a modified transcriptional program and epigenetic modifications induced during the primary response and maintained thereafter. However, under certain priming conditions, i.e. chronic infections or tumours, memory cells also up-regulate the expression of checkpoint receptors that can inhibit the display of effector functions following activation. Prediction of memory cell quality based on the expression of effector functions is thus difficult, as many studies have highlighted their co-expression with inhibitory receptors in cells unable to display their functions. We propose to address the prediction of the quality of CD8 T cell response through an original approach, built on a shared experience of computational immunology. We will use recently developed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), to generate data characterizing single CD8 T cells generated in two immunization contexts that lead to distinct protective capacity at the population level. The data generated will be analysed using state of the art methods. Molecularly homogeneous cellular subsets differentially present in these populations will be identified and their protective capacities will be characterized. To define the differentiation pathways leading to the generation of these cells, we will follow the transcriptome evolution at the single-cell-level over a memory-generation time course. These longitudinal data will be used to delineate differentiation pathways leading to the generation of these functionally defined memory subsets. They will also serve to develop and test innovative modelling tools that should help to draw and test new hypotheses on the generation of different qualities of memory cells. Gene regulatory networks will be inferred and used to implement each individual cell with a molecular model that orchestrates cell fate. State of the art methods will then be developed and used to generate a multiscale model that couples the molecular model orchestrating cell fate to a cellular dynamical model describing differentiation pathways. The resulting multiscale model should be able to predict the outcome of an immunization regimen in terms of memory cell quality and quantity from few early measurable molecular events.
This project will aggregate large amounts of already available and specifically generated expression data in a unique attempt to delineate key features of efficient protective memory CD8 T cells and the conditions regulating their generation. It will also tackle several basic issues in mathematical modelling, such as coupling different time and spatial scales. It will eventually yield a computational tool that should help pharmaceutical companies in the process of vaccine candidate screening in preclinical studies.

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Centre de Recherche Inria Grenoble - Rhône-Alpes - DRACULA Centre de Recherche Inria Grenoble - Rhône-Alpes - DRACULA

Help of the ANR 489,088 euros
Beginning and duration of the scientific project: January 2019 - 48 Months

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