Marie Dittmer

Influence of regulatory T cells on oligodendrocyte lineage cells in vitro

The process of myelin regeneration (remyelination) in the central nervous system (CNS) is still not understood in its entirety. Uncovering the mechanisms that govern remyelination will benefit patients with demyelinating diseases such as multiple sclerosis. Oligodendrocytes and oligodendrocyte precursor cells (OPCs) are the myelinating cells of the CNS and therefore play a central role in remyelination. It has been shown that cells of the adaptive immune system, particularly CD4 T cells, promote remyelination in vivo. Based on our observations that regulatory T cell (Treg) depletion impairs remyelination in vivo, we hypothesized that Tregs enhance remyelination through support of oligodendrocyte lineage cells. To test this hypothesis, Tregs were first differentiated in vitro, in parallel with non-polarized CD4 T cell controls, and supernatants from these cultures were harvested. The effects of these supernatants on OPC proliferation and maturation were then investigated in an in vitromodel ofmurinemixed glial cells. Neither Treg nor non-polarized T cell supernatant had an effect on OPC proliferation. However, Treg supernatant significantly enhanced OPC maturation, while supernatant of non-polarized T cells had no effect. These studies suggest a novel beneficial role of Tregs in remyelination through the enhancement of OPCmaturation. Recently it was uncovered that Tregs have an intrinsic repair function inmuscle regeneration that is distinct from immune modulation. A similar intrinsic function in regeneration of myelin by driving OPC maturation is likely and underlying mechanisms are currently under investigation.

Regulatory T cells promote CNS myelin regeneration in vivo

Oligodendrocytes (ODCs) are myelinating cells of the CNS which support structurally and metabolically neurons. As the degree of in vivo plasticity of mature ODCs has become a matter of debate recently, we investigated the dynamics of these cells under different kind of demyelinating stress. For this purpose, we used a mouse model (oLucR) expressing luciferase in MOG positive ODCs under the control of a beta-actin promoter. Activity of this promoter served us as surrogate for cellular dynamics through recording of in vivo bioluminescence following three different types of insult to the myelin: cuprizone-, diphtheria toxin (DTx), and MOG immunization. To our surprise, all experimental demyelination applied resulted into augmentation of ODC-specific in vivo bioluminescence. Further ex vivo analysis of LucR CNS confirmed the observed in vivo upregulation of luciferase following insults. Increase in bioluminescence upon MOG immunization was parallel to an increased transcription of tubulin, thus suggesting that ODCs can acutely increase their cytoskeletal plasticity in vivo during demyelination.