Researchers Identify Subset of Immune Cells Driving MS

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

Share this article:

Share article via email
STAT5 protein complex | Multiple Sclerosis News Today | illustration of mice in a lab

A new subset of type 3 innate lymphoid cells (ILC3s) — a type of immune cell known mostly for its anti-inflammatory and immunosuppressive effects in the gut — infiltrates the brain and promotes the abnormal immune attacks that drive multiple sclerosis (MS), according to a study in a mouse model of the disease.

“The infiltration of these inflammatory ILC3s to the brains and spinal cords of mice coincides with the onset and peak of disease,” John Benji Grigg, the study’s first author and a doctoral candidate at Weill Cornell Graduate School of Medical Sciences in New York, said in a press release.

“Further, our experimental data in mice demonstrate these immune cells play a key role in driving the pathogenesis of neuro-inflammation,” Grigg added.

Notably, blocking these brain-infiltrating cells lessened MS-like disease in animals. A similar result was obtained when the researchers boosted the activity of specific tissue-resident ILC3s, which maintained their hallmark immunosuppressive properties during MS development, highlighting two new potential therapeutic strategies for MS.

The study, “Antigen-presenting innate lymphoid cells orchestrate neuroinflammation,” was published in the journal Nature.

Recommended Reading
banner for

Can Focusing on the Epstein-Barr Virus Help Researchers Fight MS?

An autoimmune disease, MS is caused by the immune system mistakenly attacking myelin, the protective fatty sheath that wraps around nerve fibers in the central nervous system (CNS, the brain and spinal cord) and is essential for efficient nerve cell communication. Immune T-cells that wrongly recognize myelin as foreign and drive pro-inflammatory responses and immune attacks against it.

However, “the mechanisms that regulate pro-inflammatory T cells in the CNS are incompletely understood,” the researchers wrote.

Now, a team of researchers at Weill Cornell Medicine, along with colleagues in Germany and France, discovered a new subset of ILC3s that promotes T-cell-mediated abnormal immune attacks against myelin in a mouse model of MS.

ILC3s, a group of immune cells that typically reside in the gut and other organs, help the immune system tolerate beneficial microbes by suppressing inflammation and immune reactions in these organs, including those directed by T-cells.

The newly discovered ILC3 subset, which the researchers called inflammatory ILC3s, showed a distinct molecular signature relative to conventional ILC3s and was found to circulate in the bloodstream.

Notably, significantly higher levels of inflammatory ILC3s were found in the blood of MS patients and mice with MS-like disease, compared with their healthy counterparts.

These cells also significantly infiltrated the CNS in the mouse model and were detected in the cerebrospinal fluid — the liquid that surrounds the CNS — of MS patients, showing an association with brain lesions.

Further analyses in the mouse model revealed CNS-infiltrating inflammatory ILC3s were localized in close association with T-cells in brain regions of active inflammation and nerve damage, and that they worked as antigen-presenting cells.

This meant they displayed myelin fragments, or a myelin antigen, to T-tells, promoting the stimulation and growth of self-reactive, myelin-specific T-cells that could cause nerve damage and MS-like symptoms. Antigens are molecules able to trigger an immune response.

Inflammatory ILC3s’ ability to present antigens to T-cells was found to be critical for T-cell responses in the CNS and the development of MS-like disease in these mice.

Specifically, removing an essential molecule of this antigen-presenting process from ILC3s significantly reduced the frequencies and numbers of activated self-reactive, myelin-specific T-cells in the CNS and prevented the development of MS-like disease.

“Identification of inflammatory ILC3s with antigen presentation capabilities in the central nervous system of people with MS offers a new strategic target to prevent nervous system injury,” said Timothy Vartanian, MD, PhD, one of the study’s authors, a professor of neuroscience and neurology, and chief of the division of multiple sclerosis and neuro-immunology at Weill Cornell Medicine.

In contrast, conventional and tissue-resident ILC3s outside the CNS were found to retain their immunosuppressive properties and to prevent MS-like disease when modified to specifically present myelin antigens to T-cells.

Notably, conventional ILC3s are known to work as antigen-presenting cells,  but in a way that promotes immune tolerance to the displayed antigen, rather than an immune response against it.

The researchers demonstrated that promoting the display of myelin antigen by these tolerance-inducing ILC3s significantly reduced the number of self-reactive, myelin-specific T-cells in the blood and CNS and prevented the development of MS-like disease in the mice.

These findings highlight “the potency of peripheral and tissue-resident ILC3s in eliminating autoimmune T cells, inducing tolerance and protecting from neuroinflammation if experimentally targeted to present myelin antigen,” the team wrote.

Overall, the study defined “a population of inflammatory ILC3s that is essential for directly promoting T-cell-dependent neuroinflammation in the CNS and [revealed] the potential of harnessing peripheral tissue-resident ILC3s for the prevention of autoimmune disease,” the researchers wrote.

Gregory Sonnenberg, PhD, the study’s co-senior author, said these data suggest that MS and potentially many other inflammatory conditions someday could be treated either by directly suppressing the activity of inflammatory ILC3s, or by modifying conventional ILC3s to promote tolerance to specific antigens.

Sonnenberg is an associate professor of microbiology and immunology in medicine at Weill Cornell Medicine.

Dancing Doodle

Did you know some of the news and columns on Multiple Sclerosis News Today are recorded and available for listening on SoundCloud? These audio news stories give our readers an alternative option for accessing information important for them.

Listen Here