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 non-canonical, 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 transcriptional programs - then referred to as T helper-like T reg (T H -like T reg ). Unleashing T helper 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 -stabilising 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 (T FR ).