Pro-inflammatory Th17 Immune Cells Harm Myelin-producing Cells

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Pro-inflammatory T helper 17 cells, known as Th17 cells — a type of immune cell known to play a role in multiple sclerosis (MS) — directly interact with myelin-producing cells, promoting their damage and death, according to a study in a mouse model of MS and in samples from MS patients.

These damaging effects were associated with the release, by Th17 immune cells, of a molecule called glutamate, which works as a neurotransmitter, or a brain signaling molecule, in a healthy brain. Glutamate can have toxic effects when found at high levels outside cells, however.

The researchers noted that blocking CD29, a cell surface receptor protein, lessened Th17-mediated injury in myelin-producing cells.

These findings shed light on the mechanisms behind Th17 cells’ damaging effects on MS and suggest that locally suppressing CD29-triggered glutamate release in these cells may be a potential therapeutic approach for MS, according to the researchers.

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The study, “Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation,” was published in the journal PNAS by a team of researchers in Germany and Canada.

Th17 immune cells are a subpopulation of T helper cells that produce a pro-inflammatory molecule called interleukin-17 (IL-17).

In MS, the protective barrier that prevents circulating microbes, large molecules, and immune cells from reaching the central nervous system or CNS — composed of the brain and spinal cord — is damaged. That allows overactive Th17 cells to enter the CNS.

These overactive immune cells produce excessive levels of IL-17, and promote the destruction of myelin, which is the protective fatty sheath around nerve cell fibers that is progressively lost in MS.

Notably, this progressive myelin loss also is associated with the impaired function of oligodendrocytes, myelin-producing cells capable of restoring the myelin sheath — a process known as remyelination.

However, the processes leading to oligodendrocyte and myelin injury in MS “are far from being understood, and therapeutic strategies protecting the myelin compartment and promoting remyelination have been so far unsuccessful,” the researchers wrote.

To address this problem, the team now assessed the direct effects of Th17 cells on oligodendrocytes in a mouse model of MS, in brain samples of deceased MS patients, and in lab-grown human oligodendrocytes.

Using cutting-edge microscopy technology to monitor what happened in the brains of the mouse models in real-time, the researchers found that CNS-infiltrating Th17 cells directly interacted with oligodendrocytes.

Notably, 40% of all Th17–oligodendrocyte interactions lasted longer than five minutes — a period of time “known to be relevant and sufficient for initiating signaling pathways in immune interactions,” the team wrote.

Close contacts between T helper cells and oligodendrocytes also were observed in brain samples of deceased MS patients, further supporting a potential damaging role from this interaction in MS.

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Exposure to Th17 cells was found to worsen myelin loss in brain tissue of the mouse model, and promote damage and death of lab-grown human oligodendrocytes, compared with Th2 cells, which are considered to have beneficial effects in MS.

Also, T helper cells from MS patients resulted in higher toxicity toward oligodendrocytes than those from healthy individuals.

Further analyses revealed that Th17-oligodendrocyte interactions involved the CD29 receptor protein at the surface of Th17 cells and CD29 ligands at the surface of myelin-producing cells. Notably, both human and mouse Th17 cells were found to present higher CD29 levels than their Th2 counterpart.

This interaction triggered CD29-dependent release of glutamate by Th17 cells, which promoted cell stress in oligodendrocytes, affected their generation of fatty molecules, and impaired myelin production.

Moreover, the team found that blocking CD29 in Th17 cells protected lab-grown human oligodendrocytes from Th17-mediated injury, while CD29 activation boosted the immune cells’ damaging effects, increasing oligodendrocyte damage and death.

These findings suggest that “CD29-triggered glutamate release by Th17 cells contributes to [disease-causing] mechanisms underlying demyelination [myelin loss] and remyelination failure in MS,” the researchers wrote.

They also “provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities to protect oligodendrocytes’ myelinating processes in MS,” the team added.

However, future studies focused on CD29 suppression “should address specific modifications of CD29 without systemic neutralization to limit side effects on physiological functions of CD29,” the researchers concluded.

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