Investigating the cellular and molecular mechanisms of T cell-mediated myelin regeneration

Abstract

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS), characterised by the loss of myelin and oligodendroglia (demyelination). Although myelin regeneration (remyelination) can occur in MS, it often fails, leaving axons vulnerable to degeneration. In patients, this leads to disease progression and subsequent disability. At present, there is no cure for MS, but there are some disease-modifying therapies that can reduce relapses. With no therapies enhancing remyelination, it is therefore essential to uncover the mechanisms that regulate this process. Previously, CD4+ T cells have been shown to play a central role in MS pathology. We have since reported that regulatory T cells (Treg) can drive oligodendrocyte progenitor cell (OPC) differentiation and remyelination. The molecular mechanism(s) underlying this effect remain mostly unknown but have been linked to MCAM and Itga2. The role of major histocompatibility complex class II (MHC-II) is also well known in this T cell immune response, but not in the context of regeneration. In MS, MHC-II is highly expressed in de- and remyelinating lesions and can be upregulated by glial cells important to myelin regeneration (microglia, astrocytes, and oligodendrocytes). To further understand the functional significance of MHC-II in the CNS, this study aimed to investigate its role in (1) murine CNS development, (2) remyelination, and (3) in CD4+ T cell-driven repair. For this, we examined oligodendrocyte differentiation, remyelination and glial cell dynamics in the CNS of WT and MHC-II-deficient mice. Interestingly, we found that MHC-II was expressed in the developing murine CNS by microglia/macrophages and mature/myelinating oligodendrocytes (OLs). Despite this expression, myelination in MHC-II-deficient mice was comparable to WT controls. In WT spinal cord lesions, MHC-II was upregulated during de- and remyelination. However, the deficiency of MHC-II significantly decreased the number of myelin wrapped axons, microglia/macrophages, and total astrocytes. For microglia/macrophages, impairments in proliferation were rescued by adoptively transferred Treg in an MHC-II-independent manner. In vitro, Treg significantly enhanced OPC differentiation, again independent of MHC-II, but only when in physical contact with OPCs. Finally, activated CD4+ T cells were observed in MHC-II-deficient lesions. Taken together, the results of this thesis suggest a novel MHC-II-independent mechanism of Treg-driven OPC differentiation, and a possible requirement for Treg in the microglial/macrophage response to demyelination. Although further research is needed to identify the mechanism(s) by which Treg promote regeneration, this work suggests that CD4+ T cells may have the capacity to function beyond what is classically known in MS; biological knowledge that may prove invaluable for the development of remyelinating therapies.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Wellcome Trust & Northern Ireland Department for the Economy
Supervisor	Denise Fitzgerald (Supervisor), Beckie Ingram (Supervisor), Yvonne Dombrowski (Supervisor) & Alerie Guzman de la Fuente (Supervisor)