Novel immune cell population may trigger MS inflammation

December 17, 2021
A group of immune cells that normally protect against inflammation in the gastrointestinal tract may have the opposite effect in multiple sclerosis, according to a new study. The results suggest that countering the activity of these cells could be a new therapeutic approach for MS.

The Weill Cornell Medicine and NewYork-Presbyterian researchers were studying a set of immune cells called group 3 innate lymphoid cells. These cells help the immune system tolerate beneficial microbes and suppress inflammation in the intestines and other organs throughout the body. Researchers discovered a unique subset of these cells that circulate in the bloodstream and can infiltrate the brain — and, to their surprise, do not quench inflammation but instead ignite it.

The scientists called this subset inflammatory ILC3s, and found them in the central nervous system of mice with a condition modeling MS. Instead of constraining the immune response, this subset of ILC3s spurred T cells to attack myelinated nerve fibers, leading to MS-like disease symptoms. The researchers detected similar inflammatory ILC3s in the peripheral blood and cerebrospinal fluid of MS patients.

The researchers have shown in recent work that ILC3s residing in the gut act as sentinels and immune regulators, suppressing inflammation — including inflammatory T-cell activity — and warding off cancer. In the new study, they examined the roles of ILC3s in the brain and found that ILC3s are not normally present in the brain under healthy conditions but can infiltrate the brain from the bloodstream during inflammation. When they do infiltrate the central nervous system, they have proinflammatory rather than anti-inflammatory effects.

The researchers showed these inflammatory ILC3s in the brain function as antigen-presenting cells. They display bits of myelin protein, the main ingredient in the insulating layer around nerve fibers, to T cells — prompting them to attack myelin, causing the nerve damage that gives rise to disease signs. They found the inflammatory ILC3s in close association with T cells in regions of active inflammation and nerve damage in the mouse brains.

The researchers discovered they could prevent MS-like disease in the animals by removing from the ILC3s a key molecule called MHCII, which normally is used in the antigen-presenting process — the removal blocks the cells’ ability to activate myelin-attacking T cells. Finally, the researchers discovered that ILC3s that reside in other tissues in the body can be programmed, in effect, to counter the activity of brain-infiltrating T cells, preventing the MS-like condition disease in mice.

This work was completed in close collaboration with the Institute for Molecular Medicine at the University Medical Center of Johannes Gutenberg University Mainz, where the researchers built on prior research demonstrating that there are gut-resident ILC3s that display antigens to T cells in a slightly different way to promote T-cell inactivity, or “tolerance.” The researchers demonstrated that by experimentally exposing these tolerance-inducing intestinal ILC3s to myelin, they could block neuroinflammatory T-cell activity and the development of MS-like disease in the mice.

Results of mouse model studies sometimes do not translate to humans. However, the researchers said the work points to the possibility that MS could someday be treated either by directly inhibiting the activity of inflammatory ILC3s that infiltrate the brain, or by targeting self-antigens to the intestinal ILC3s that promote tolerance in other tissues.

The findings were published in the journal Nature.

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