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Title: Influence of regulatory T cells on oligodendrocyte lineage cells
Author: Dittmer, Marie
ISNI:       0000 0004 6425 2602
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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One of the greatest unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS). Uncovering the mechanisms that govern remyelination and developing novel treatments will prove highly beneficial to patients’ quality of life. Oligodendrocytes, the myelinating cells of the CNS, play a central role in remyelination and originate from oligodendrocyte progenitor cells (OPCs). It has been shown that cells of the adaptive immune system, particularly CD4+ T cells, promote remyelination in vivo however the contributions of distinct T cell subsets are currently not known. Based on previous observations by the group that depletion of regulatory T cells (Treg) impairs remyelination in vivo, we hypothesised that Treg enhance remyelination through a direct effect on oligodendrocyte lineage cells. To test this hypothesis, murine Treg were first activated and differentiated in vitro, in parallel with activation of non-polarised CD4+ T cell controls (NP), and media from these cultures were harvested. The effects of these conditioned media on OPC proliferation, survival and differentiation was investigated using in vitro models of murine mixed glial cells and pure OPCs. Neither Treg- nor NP-conditioned media had an effect on OPC proliferation and survival. However, Treg-conditioned media directly enhanced OPC differentiation in both mixed glial and pure OPC models, whereas NP-conditioned media did not. These findings suggest that Treg secrete a factor that directly enhances OPC differentiation. Confirming that the OPC differentiation-enhancing effect of Treg was indeed protein-mediated, we showed for the first time that Treg produce CCN3, a protein which is best known for its role in promoting angiogenesis. Upon treatment with a CCN3 antibody, CCN3-depletion or treatment with CCN3-/- Treg-conditioned media, the OPC differentiation-enhancing effect of Treg was abolished in mixed glial cultures. However, in pure OPC cultures there was no such effect of these three different loss of function approaches. This suggests Treg-derived CCN3 does not mediate the direct Treg-enhancing effect on OPC differentiation, but an additional indirect effect potentially mediated by other cell types present in mixed glial cultures. Pilot studies suggest, that the direct OPC differentiating effect of Treg may be partially mediated via JAK/STAT and MAPK signalling pathways. These studies uncover a novel, beneficial role of Treg in remyelination through the direct enhancement of OPC differentiation. We show that Treg have a direct differentiating effect on a CNS progenitor cell population, and therefore the potential to play an intrinsic role in regeneration, that is distinctly different from known immunomodulatory functions of Treg. This new knowledge could prove invaluable in the development of novel remyelination-enhancing therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available