Model-Based Assessment of the Role of Uneven Partitioning of Molecular Content on Heterogeneity and Regulation of Differentiation in CD8 T-Cell Immune Responses

Abstract

Activation of naive CD8 T-cells can lead to the generation of multiple effector and memory subsets. Multiple parameters associated with activation conditions are involved in generating this diversity that is associated with heterogeneous molecular contents of activated cells. Although naive cell polarisation upon antigenic stimulation and the resulting asymmetric division are known to be a major source of heterogeneity and cell fate regulation, the consequences of stochastic uneven partitioning of molecular content upon subsequent divisions remain unclear yet. Here we aim at studying the impact of uneven partitioning on molecular-content heterogeneity and then on the immune response dynamics at the cellular level. To do so, we introduce a multiscale mathematical model of the CD8 T-cell immune response in the lymph node. In the model, cells are described as agents evolving and interacting in a 2D environment while a set of differential equations, embedded in each cell, models the regulation of intra and extracellular proteins involved in cell differentiation. Based on the analysis of in silico data at the single cell level, we show that immune response dynamics can be explained by the molecular-content heterogeneity generated by uneven partitioning at cell division. In particular, uneven partitioning acts as a regulator of cell differentiation and induces the emergence of two coexisting sub-populations of cells exhibiting antagonistic fates. We show that the degree of unevenness of molecular partitioning, along all cell divisions, affects the outcome of the immune response and can promote the generation of memory cells.

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“…Crauste et al expanded on this initial model of T cell maturation in subsequent papers (Barbarroux, Michel, Adimy, & Crauste, 2018;Gao et al, 2016;Girel et al, 2019). The authors applied the model to predict the effects of exogenous IL-2 levels and the threshold value of the activated IL-2:IL-2R complex needed for a preactivated T cell to transition to an activated cell (Gao et al, 2016).…”

“…Their simulations show that both IL-2 supplementation and the cells' sensitivity to IL-2R activation tune the duration of T cell-APC interaction, which directly influences T cell fate and phenotype (the concentrations of intracellular species). Recently, Crauste and coworkers (Girel et al, 2019) built on this model to add memory T cells and the transcription factor Eomesodermin (Eomes), which plays an important role in the formation of memory T cells (Kaech & Cui, 2012). They use the expanded model to study how intracellular heterogeneity (variability in the concentrations of Tbet and Eomes) affects cell division.…”