Regulatory T-cell stability and functional plasticity in health and disease

FOXP3-expressing regulatory T cells (T_reg ) are indispensable for immune homeostasis and tolerance, and in addition tissue-resident T_reg have been found to perform noncanonical, tissue-specific functions. For optimal tolerogenic function during inflammatory disease, T_reg are equipped with mechanisms that assure lineage stability. T_reg lineage stability is closely linked to the installation and maintenance of a lineage-specific epigenetic landscape, specifically a T_reg -specific DNA demethylation pattern. At the same time, for local and directed immune regulation T_reg must possess a level of functional plasticity that requires them to partially acquire T helper cell (T_H ) transcriptional programs-then referred to as T_H -like T_reg . Unleashing T_H programs in T_reg , however, is not without risk and may threaten the epigenetic stability of T_reg with consequently pathogenic ex-T_reg contributing to (auto-) inflammatory conditions. Here, we review how the T_reg -stabilizing epigenetic landscape is installed and maintained, and further discuss the development, necessity and lineage instability risks of T_H 1-, T_H 2-, T_H 17-like T_reg and follicular T_reg .