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Title: The role of regulatory T cells and CCN3 in CNS myelination and remyelination
Author: O'Hagan, Thomas P.
ISNI:       0000 0004 6499 9001
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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Multiple Sclerosis (MS) is an immune-mediated disease, characterised by demyelination in the central nervous system (CNS)- In MS, the regeneration of myelin sheaths (remyelination) can occur. However, when this regenerative process fails, patients can develop permanent disability. The promotion of remyelination is currently an unmet clinical need that holds significant potential to improve the lives of MS patients. Despite the pathological role of CD4+ T cells in MS, T cells have been shown to support remyelination in experimental models. However, previous studies have investigated total CD4+ T cells without addressing distinct CD4+ T cell subsets. CD4+ Regulatory T cells (Treg) have been identified in multiple organ systems as having a role in repair and regeneration; therefore, we aimed to characterise the role of the anti-inflammatory, CD4+ T cell subset, Treg, in CNS remyelination. To determine if Treg have a direct effect on neural cells we utilised an organotypic brain stem slice model that myelinates ex vivo. In both inflammatory and stabilised brain slice cultures, Treg and/or conditioned media from Treg cultures promoted the maturation of oligodendrocytes, developmental myelination and remyelination as measured by the co-localisation of fluorescent staining of myelin and axons. Treg-deficient mice exhibited impaired oligodendrocyte differentiation during remyelination that was rescued by the adoptive transfer of Treg in vivo. Proteome profiling of conditioned media identified CCN3 as a novel Treg-derived factor that promoted myelination and was required for Treg-enhanced myelination in brain slices. This is the first evidence of CCN3 in CNS regeneration and of CCN3 production by T cells. These findings uncover a new role of Treg in promoting oligodendrocyte differentiation and remyelination in the CNS, distinct from, but complementary to, the classical anti-inflammatory roles of Treg.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available