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

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