Dynamics of T-helper cell differentiation and plasticity: How have computational models improved our understanding?

Abstract

Naïve CD4+ T cells can polarize into diverse functionally distinct effector cell types such as Th1, Th2, Th17 and Treg. These cell types can also interconvert among one another. The dynamics of T-cell differentiation and plasticity is driven by complex interactions involving many feedback loops among cytokines, intracellular signalling and lineage-determining transcription factors. In the past two decades, mechanistic computational models have played an instrumental role in understanding the underlying emergent dynamics. Here, we highlight the key concepts elucidated from such modelling efforts – a) multistability in underlying gene regulatory networks, b) the (co-) existence of stable hybrid cell states (Th1/Th2, Th1/Th17, Th2/Th17), and c) population-level dynamics of T-cell differentiation. These models, in close integration with experimental data, have improved our understanding of cell-state transitions and trajectories implicated in intracellular and population dynamics of T-cell plasticity.