Tissue repair in the central nervous system: the epigenetic programming of regulatory T cells

Regulatory T cells are well known for their immunomodulatory role but also their regenerative function is increasingly recognized across multiple tissue types including skeletal muscle, lung and the central nervous system (CNS). In the CNS, Tregs have been shown to promote oligodendrocyte precursor cell differentiation and their interaction with microglia supports a pro-regenerative microenvironment in the brain. The suppressive function of Tregs is highly dependent on the epigenetic signature, specifically DNA methylation, of certain network of Treg-related genes including FOXP3, CTLA4, IKZF2, IKZF4 and TNFRSF18 which collectively function to maintain Treg cell lineage and stability. Whether a similar or the same epigenetic program also influences the regenerative capacity of Tregs remains unknown, and the methylation status of regenerative genes such as AREG, NT3, and osteopontin has never been characterized. Understanding the epigenetic regulation of Tregs in this respect is relevant for demyelinating disease such as multiple sclerosis (MS). MS is characterized by chronic neuroinflammation and neurodegeneration associated with remyelination failure. In MS, Treg suppressive function is compromised and epigenetic dysregulation at key Treg loci has been reported. However, the role of those loci in repair is unknown and the methylation status of regenerative genes in MS Tregs has not been studied. This review examines the evidence for Treg-mediated CNS repair, the epigenetic mechanisms controlling Treg identity, and highlights the epigenetic regulation of Treg regenerative genes as a critical gap in the field with potential implications for remyelination failure in MS.