Regulatory T cells as drivers of CNS remyelination: neuro-immune cross-talk and comparative insights from mammalian and zebrafish models

Demyelination of the Central Nervous System (CNS) is a pathological process that causes the destruction of the myelin sheath, the insulating cover that protects the nerve fibres. This serves as one of the major attributes of numerous neurological disorders, such as Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorder (NMOSD), Acute Disseminated Encephalomyelitis (ADEM), Myelin Oligodendrocyte Glycoprotein-related antibody disease (MOGAD), etc. It is usually initiated as an immune-mediated injury to myelin, followed by dysregulation of the immune system and ultimately failure of effective remyelination. Although oligodendrocytes in the CNS have some capacity for regeneration, the surrounding microenvironment severely inhibits their function, which results in a reduced regenerative outcome. Previously referred to as suppressor T cells, regulatory T cells (Tregs) are a subset of T cells that were traditionally thought to have an immunosuppressive function. However, it has just recently been shown that they directly contribute to regeneration and repair. The goal of this review is to demonstrate how Tregs can promote regeneration by balancing a variety of underlying molecular and cellular processes. Recent research shows that Tregs affect oligodendrocyte lineage progression, microglial and astrocytic responses, and the milieu around the demyelination site in order to perform remyelination. These effects are age-dependent and occur both temporally and geographically. In order to offer an evolutionary perspective on the conserved immune-mediated regenerative pathways that may be diminished in mammals and can be further investigated for therapeutic purposes, this review also aims to draw comparisons between the mechanisms used by regeneration-competent and non-competent species.