Harnessing T cells to remyelinate the central nervous system.

The central question of my long-term research programme is: How does the immune system influence brain repair? More specifically, what roles do immune cells play in the repair of myelin in the central nervous system (CNS)? Myelinrepair is a natural regenerative and usually efficient process, accomplished by oligodendrocytes (OL), which confers immense benefit by restoring and retaining efficient neurological function. Accumulating evidence demonstrates key roles for immune signalling in efficient remyelination and complete deficiencyof T cells decreases remyelination. In the past decade many new subsets of T cells have been characterised, that exert diverse and often opposing biological effects in immunity and tissue repair. This suggests that some T cell subsets may support, while other subsets may inhibit, remyelination. Indeed we have recently discovered that regulatory T cells (Treg) promote oligodendrocyte differentiation, myelination and remyelination in part throughproduction of CCN3, a protein with known regenerative functions. Current understanding of T cell biology coupled with our recent findings provide the rationale for our hypothesis that T cell subsets differentially influence CNS remyelination and may be exploited for therapeutic gain. To test this hypothesis we will address the following research questions: 1. How does CCN3 mediate Treg-induced oligodendrocyte differentiation/remyelination? 2. Do human Treg promote oligodendrocyte differentiation in general and in Multiple Sclerosis? 3. What effects do other T cell subsets (Th1, Th2, Th22, Tfh) have on oligodendrocyte lineage cells and CNS remyelination?