Antigen-Presenting Immune Cells May Trigger Neuroinflammation

A group of immune cells that normally protect against inflammation in the gastrointestinal tract may have the opposite effect in multiple sclerosis (MS) and other brain inflammation-related conditions, according to a new study by Weill Cornell Medicine and NewYork-Presbyterian researchers.  The researchers, who reported their findings in Nature, discovered a unique subset of innate lymphoid cells (ILC3s) that circulate in the bloodstream and can infiltrate the brain—and, to their surprise, do not quench inflammation but instead ignite it.

 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, contrary to their expectation, 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 pro-inflammatory rather than anti-inflammatory effects.

The team showed with a mouse model of MS that these inflammatory ILC3s in the brain function as antigen-presenting cells: They display bits of myelin protein 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 infiltration of these inflammatory ILC3s to the brains and spinal cords of mice coincides with the onset and peak of disease,” said first author John Benji Grigg. “Further, our experimental data in mice demonstrate these immune cells play a key role in driving the pathogenesis of neuroinflammation.” The researchers discovered that 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 essentially blocks the cells’ ability to activate myelin-attacking T cells.

Finally, the scientists 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.