TREGeneration

The complexity of the central nervous system (CNS) and our lack of understanding about its potential regenerative capabilities, mean that degenerative diseases such as multiple sclerosis (MS) – where the myelin sheaths of neurons degrade – have no cure. Pioneering researchers at Queen’s University Belfast have been digging into demyelination and have revealed a new function for a subset of immune cells called regulatory T cells (Tregs) in the CNS: the ability to promote myelin regeneration (1). To learn more, we spoke with Denise Fitzgerald, lead investigator and senior lecturer at Queen’s University Belfast.

What prompted you to investigate myelin regeneration?

Myelin regeneration (remyelination) can be a very efficient and effective process that restores function, but sometimes it fails and when it does, we have no therapeutics directed towards boosting remyelination – leaving a major unmet need for demyelinating conditions, such as MS. As an immunologist, I had researched how immune cells – particularly T cells – were involved in myelin damage, but there was very little information on how T cells influence myelin regeneration, so I felt that we could address some knowledge gaps. I thought that if we could identify how myelin is naturally regenerated, we could use that information to design potential new therapies to increase remyelination.

What do your findings mean for regenerative medicine?

Our results point to Tregs as key players in myelin regeneration. These cells have been identified as important in other regenerative sites – muscle and lung, for example – so our work increases the evidence that these cells play a role in tissue regeneration. What is striking, however, is that these cells may use different regenerative mechanisms in different tissues – it will be important to identify which aspects are tissue-specific mechanisms and mediators.

In our CNS studies, we identified the protein CCN3 as being a key product of Tregs that enhanced myelin production – which was surprising because i) the protein had not previously been known to be produced by T cells of any type, and ii) it was not known to be important in remyelination. In our experiments, we also found that neutralising/removing CCN3 was enough to abrogate the regenerative functions from Treg cells. As a T cell biologist, I expected that it would be a combination of factors or that compensatory mechanisms would be at play – and that may still be the case in more complex in vivo experimental models.

What were the main challenges?

As an immunology research group, we had to establish new techniques, which was only possible because we had fantastic support from our neuroscience collaborators. It was also incredibly challenging to design experiments that target Tregs in a way that modulates the regenerative phase of the experimental models, without solely reducing the extent of damage – in other words, reducing the initial myelin damage through immunomodulation is not the same as boosting regeneration. In the case of MS, we already have therapeutics that reduce damage with little impact on myelin regeneration. Thus, we have to ensure that our preclinical studies are truly identifying changes in regeneration rather than changes in initial burdens of damage.

What’s next?

We have several new projects that spawned as a result of this study, such as our translational work in human experimental models – examining interactions between different types of human Tregs and oligodendrocyte progenitor cells. We are also studying CCN3 in health and disease to determine its therapeutic development potential and its importance in general CNS function, as well as during de/remyelination. Another study is examining the molecular mechanisms of immune-mediated oligodendrocyte differentiation, the roles of other T cell subsets in myelin regeneration – as well as some slightly quirkier ideas that are at early stages so we can’t quite discuss them yet... We are very grateful to the Wellcome Trust and BBSRC who are supporting our research programme.