Advancing age affects Tregs’ ability to promote myelin repair: Study

While regulatory T-cells (Tregs) are able to promote remyelination — the repair of the myelin sheath that’s damaged in multiple sclerosis (MS) — this ability declines significantly with age, a new study shows.

Based on the findings, researchers have identified molecular targets that may boost the myelin-repairing features of Tregs, which could be useful for future research into treatments for MS and other demyelinating diseases.

The study, “Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination,” was published in Nature Communications.

Myelin is a fatty covering around nerve fibers that helps them send electrical signals. “It is similar to the plastic that covers the copper in a cable,” Alerie Guzmán de la Fuente, PhD, co-author of the study at Institute for Health and Biomedical Research of Alicante (ISABIAL) in Spain, said in a news release.

MS is caused by inflammation in the brain and spinal cord that damages myelin. Promoting remyelination is a major goal for MS research.

Tregs are immune cells that help regulate the immune system. Recent research has suggested they may aid remyelination. Specifically, Tregs seem to help promote immature oligodendrocyte precursor cells (OPCs) grow into mature oligodendrocytes, the cells chiefly responsible for making new myelin in the brain and spinal cord.

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An ‘aged environment’s’ effect on Tregs

It’s long been known that remyelination in the brain becomes less efficient as a person gets older, but the biological reasons aren’t well understood. Here, scientists examined mice that were 3 to 4 months old — young adulthood for a mouse — and compared them with 15-to-18-month-old mice, roughly the same age as a person who’s around 65 to 70, to see if Tregs’ ability to promote oligodendrocyte maturation changes with age.

They found that older mice have more Tregs in their brain and spinal cord, but were less able to promote myelin repair. When the mice were given treatments to increase Treg numbers, the increase only led to a gain in mature oligodendrocytes in young mice, but not aged mice.

In further experiments where the researchers isolated Tregs from the mice and grew them alongside OPCs in a lab, Tregs from young mice similarly promoted the immature OPCs to grow into mature myelin-making oligodendrocytes, but Tregs from elderly mice didn’t. The data collectively “suggest that aged [Tregs] fail to significantly drive myelin production,” wrote the researchers, who suggested the cells may undergo some sort of irreversible change with age that makes them less able to promote myelin repair.

Unexpectedly, when the researchers took Tregs from aged mice and put them in Treg-depleted young mice, the aged Tregs were able to promote oligodendrocyte maturation and myelin repair just as well as young Tregs. However, when Tregs from young mice were put into aged mice, they had some ability to promote oligodendrocyte activity, though not as much as when the cells were in young mice.

The results suggest elderly Tregs still have the capacity to promote myelin repair, but aren’t getting the right molecular cues to do so in an aged environment, meaning it may be possible to restore the myelin-regenerating properties of old Tregs with medication.

In final tests, the researchers found that two proteins, MCAM and ITGA2, are expressed by Tregs at progressively lower levels as the cells get older. The proteins, it was shown, are involved in the molecular signaling by which Tregs trigger OPCs to mature into myelin-making oligodendrocytes.

When aged Tregs were transferred into young mice, they started expressing higher levels of the two proteins, especially ITGA2. In cell experiments, treatment with purified ITGA2 was sufficient to promote OPC growth into mature oligodendrocytes.

“Our results identify ITGA2 as a mediator of Treg-driven OPC differentiation that is decreased with age and can directly promote OPC differentiation,” wrote the researchers, who said the mechanism require more study to see if they “hold therapeutic potential for patients with demyelinating diseases.”