Maintenance of Regulatory T Cell Identity at Sites of Inflammation Through Epigenetic Imprinting

Thomas Korn, Full professor of Neuroimmunology and Deputy Director, Department of Neurology, Klinikum rechts der Isar, Technical University Munich. 

Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. We here establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. We deciphered a series of molecules whose essential function for the preservation of Treg cell identity in the CNS we tested in loss-of-function approaches in experimental autoimmune ecephalomyelitis (EAE), the animal model of human multiple sclerosis. We identified a non-redundant transcriptional modulator that controlled an epigenetic pathway to keep the conserved non-coding region (CNS2) of the Foxp3 locus demethylated. Upon ablation of that modulater, CNS2 was methylated in Foxp3+ Treg cells in the inflamed CNS and subsequently, CNS Treg cells lost Foxp3 expression (and thus their identity as Treg cells) and acquired the capacity to produce proinflammatory cytokines including IL-17 that led to lethal EAE. In summary, we identified a druggable pathway to modulate the stability of Foxp3+ Treg cells in non-lymphoid tissues, which might be exploited both in organ specific autoimmunity but also in cancer where dysbalanced Treg cell responses prompt inappropriate immune reactions.