Chromatin-Mediated Priming of Cell Fate Potential and Plasticity for T Cell Function and Immune Tolerance

Multicellular organisms rely on their constituent cells to adopt distinct fates and maintain stable identities and functions. At the same time, cells retain a degree of flexibility — or plasticity — that allows them to alter their fate or function to respond to developmental cues, regenerate damaged tissues, and adapt to changing environments. This work investigates how chromatin dynamics and gene regulatory networks shape cell fate potential and plasticity, focusing on two cell types in the thymus that leverage these mechanisms to support immune function and tolerance. In developing thymocytes, we show that the enhancer landscapes of diverse effector T cell programs are established early in development, before antigen receptor signaling or lineage commitment, through transcription factor–directed, ATP-dependent chromatin remodeling. Next, in medullary thymic epithelial cells, which embrace transcriptional plasticity to ectopically express genes from diverse peripheral tissues and promote immune tolerance, we show that this ectopic gene expression is driven by stochastic fluctuations in chromatin accessibility. Finally, we present a dynamical systems model that formalizes how chromatin dynamics interact with transcription factor networks to generate stable, yet flexible, developmental outcomes. Together, these studies reveal how chromatin-mediated regulation of cell fate potential and plasticity enables robust yet flexible control of cellular identity — principles that may extend across development, immunity, and disease.