Regulatory T Cells Directly Promote Remyelination

The common denominator of chronic demyelinating diseases, such as Multiple Sclerosis (MS), is the gradual breakdown of myelin. Myelin is a protein that surrounds axons of neurons and acts as an insulating substance, ensuring the integrity of signals transferred from neuron to neuron. In the central nervous system oligodendrocytes are responsible for the production of myelin. However, in MS both myelin and oligodendrocytes are attacked by the host's own immune system, particularly by a group of white blood cells called effector T cells. Another subset of T cells, the regulatory T cells (Tregs), can modulate the immune system’s responses and downregulate the activity of effector T cells. Previous research has suggested that Tregs might be crucial for effective remyelination in the brain, however very little was known about the mechanisms involved.

A recent study led by Dr Yvonne Dombrowski and Dr Denise Fitzgerald at Queen's University, Belfast, reveals that Tregs play a key role in remyelination and produce crucial factors that promote myelin regeneration in the brain after injury. The breakthrough study published in Nature Neuroscience opens new horizons for the treatment of demyelinating diseases like MS.

Read also:  studying immune cells in MS patients to predict disease progression

Treg cells are required for the differentiation of myelin-producing oligodendrocytes

 The team used an acute demyelination mouse model by injecting a toxin in the spinal cord, which mimics the effects of demyelinating diseases in the central nervous system. They observed that just 3 days post lesion, Treg cells were present in the demyelinated tissue. This observation raised an important question: are Treg cells functionally important in remyelination?

To answer this question, Dr Yvonne Dombrowski and the team utilized a transgenic mouse model that lacks Treg cells. These Treg-deficient animals presented with a significantly lower number of myelin-producing oligodendrocytes, whereas the number of their precursors at the lesion site was the same. This suggests that the reduction in oligodendrocytes was likely to due to problems in the precursor's development into mature oligodendrocytes. Formation of new myelin was also substantially impaired. In the reverse gain-of-function experiment, Treg administration in Treg-deficient mice restored the oligodendrocyte population and remyelination.

The researchers concluded that Tregs, apart from their well-established immunomodulatory role, are also involved in the process of oligodendrocyte differentiation and CNS remyelination.

Learn more: manipulating Tregs to fight cancer

Direct CNS remyelination mediated by Treg cells

Looking in greater detail, the team asked whether Treg cells exert direct regenerative effects within the brain. They used organotypic brain cultures, a very useful tool that simulates the 3D organization of the brain in a dish, and makes it easier to study the interaction between immune cells, glia and neurons.

The team made a crucial observation: the production of myelin was accelerated when adding Treg cells onto the slides, or even just by adding the products released by those cells.

Was this effect mediated by the Treg cells directly, or is it possible that other types of glial cells present in the organotypic slice were involved? To answer this question Dr Fitzgerald’s collaborators in UCSF (University of California San Francisco) used cell cultures containing only oligodendrocyte progenitors and neurons. They treated them with products released by Tregs and soon after the oligodendrocyte progenitors began to give rise to mature oligodendrocytes, which was followed by an increase in neuronal myelination.

This set of experiments demonstrated that Tregs directly promote myelination, which is a different role from their classical immunomodulation, and has not been previously described.

CCN3 -the key molecule that promotes myelination

 In search of a mechanism, the team performed a detailed analysis of the proteins secreted by Tregs. They focused specifically in factors that were known to play a role in regeneration in other types of tissue. Among the molecules they studied, they singled out a protein called CCN3, which has previously been implicated in regeneration of various tissues but not in the CNS.

The researchers then added an antibody that binds to and neutralizes CCN3 onto the organotypic brain slices. The inhibition of CCN3 abolished the Treg-mediated oligodendrocyte maturation and myelination. 

Dr Fitzgerald and her team concluded that CCN3 was the key molecule produced by Tregs to induce myelination.

Therapeutic Implications

Although it is still early to say whether these exciting findings will translate into human studies, the discovery of this novel role of Tregs helps us better understand how the process of how myelination works. This may help in the development of novel therapies to stimulate myelin repair and ultimately reverse the damage in diseases like MS.

More on MS therapies: antibody-based drug to treat MS

Reference:

Dombrowski, Y., O’Hagan, T., Dittmer, M., Penalva, R., Mayoral, S.R., Bankhead, P., Fleville, S., Eleftheriadis, G., Zhao, C., Naughton, M., et al. (2017). Regulatory T cells promote myelin regeneration in the central nervous system. Nat. Neurosci. 20, 674–680. https://www.nature.com/neuro/journal/v20/n5/full/nn.4528.html