T-cell commitment inheritance – an agent-based multi-scale model

Abstract

ABSTRACTT-cell development provides an excellent model system for studying lineage commitment from a multipotent progenitor. The intrathymic development process has been thoroughly studied. The molecular circuitry controlling it has been dissected and the necessary steps like programmed shut off of progenitor genes and T-cell genes upregulation have been revealed. However, the exact timing between decision-making and commitment stage remains unexplored. To this end, we implemented an agent-based multi-scale model to investigate inheritance in early T-cell development. Treating each cell as an agent provides a powerful tool as it tracks each individual cell of a simulated T-cell colony, enabling the construction of lineage trees. Based on the lineage trees, we introduce the concept of the last common ancestors (LCA) of committed cells and analyse their relations, both at single-cell level and population level. In addition to simulating wild-type development, we also conduct knockdown analysis. Our simulations showed that the commitment is a three-step process over several cell generations where a cell is first prepared by a transcriptional switch. This is followed by the loss of the Bcl11b-opposing function two to three generations later which is when the decision to commit is taken. Finally, after another one to two generations, the cell becomes committed by transitioning to the DN2b state. Our results showed that there is inheritance in the commitment mechanism.