Researchers at Washington University School of Medicine in St. Louis have made the surprising finding that specific cells of the immune system can affect both mind and body. Their research in mice demonstrated that the T cells in the meninges surrounding the brain may act as a key link between the two, producing the cytokine IL-17, which signals to neurons, to regulate anxiety-like behaviors.

“The brain and the body are not as separate as people think, said Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff distinguished professor of pathology and immunology and a professor of neurosurgery, neurology, and neuroscience, and who is senior author of the team’s published paper in Nature Immunology. “What we’ve found here is that an immune molecule—IL-17—is produced by immune cells residing in areas around the brain, and it could affect brain function through interactions with neurons to influence anxiety-like behaviors in mice. We are now looking into whether too much or too little of IL-17 could be linked to anxiety in people.”

Kipnis and colleagues reported on their research in a report titled, “Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons.”

IL-17 is a cytokine signaling molecule that orchestrates the immune response to infection by activating and directing immune cells. IL-17 has also has been linked to autism in animal studies, and to depression in people, the authors wrote. “Interleukin (IL)-17a has been highly conserved during evolution of the vertebrate immune system, and widely studied in contexts of infection and autoimmunity. Studies suggest that IL-17a promotes behavioral changes in experimental models of autism and aggregation behavior in worms.”

How an immune molecule like IL-17 might influence brain disorders, however, is something of a mystery, given that there isn’t much of an immune system in the brain. The few immune cells that do reside in the brain also don’t produce IL-17.

Kipnis, along with first author and postdoctoral researcher Kalil Alves de Lima, PhD, realized that the meninges—tissues that surround the brain—are teeming with immune cells, and among them, a small population known as gamma delta (γδ ) T cells produce IL-17. “Recently, a rich diversity of immune cells in the healthy mouse meninges have been described, where they are ideally positioned for immune surveillance of the central nervous system (CNS) and its borders,” the investigators explained. “Meningeal immune cells, and their derived cytokines, have also been shown to affect brain functions, including sociability and spatial learning.”

Kipnis and Alves de Lima set out to determine whether these meningeal γδ T cells might have an impact on behavior. “ … we sought to identify and explore additional meningeal immune populations with the potential to impact brain functions,” they wrote. While both researchers are both now at Washington University, Kipnis and Alves de Lima conducted their studies while they were at the University of Virginia School of Medicine.

Through studies in mice, they discovered that the meninges are rich in γδ T cells and that such cells, under normal conditions, continually produce and fill the tissues surrounding the brain with IL-17. To determine whether γδ T cells or IL-17 could affect behavior, Alves de Lima put mice through established tests of memory, social behavior, foraging, and anxiety. The results showed that mice lacking γδ T cells or IL-17 were indistinguishable from mice with normal immune systems on all measures, except anxiety. In the wild, open fields leave mice exposed to predators such as owls and hawks, so they’ve evolved a fear of open spaces. The researchers conducted two separate tests that involved giving mice the option of entering exposed areas.

They found that the mice with normal amounts of γδ T cells and levels of IL-17 kept themselves mostly to the more protective edges and enclosed areas during the tests. In contrast, mice without γδ T cells or IL-17 ventured into the open areas, a lapse of vigilance that the researchers interpreted as decreased anxiety. The scientists also discovered that neurons in the brain have receptors on their surfaces that respond to IL-17. When the scientists removed those receptors so that the neurons could not detect the presence of IL-17, the mice showed less vigilance.

Neurons (green) in a mouse brain have a receptor (cyan) that detects the immune molecule IL-17. Researchers at Washington University School of Medicine in St. Louis have discovered that a molecule produced by the immune system acts on the brain to change the behavior of mice. [Kalil Alves de Lima and Mackenzie Lemieux]

The researchers say the findings suggest that behavioral changes are not just a byproduct, but are an integral part of neuro-immune communication. Although the investigators did not expose mice to bacteria or viruses to study directly the effects of infection, they injected the animals with lipopolysaccharide, a bacterial product that elicits a strong immune response.

They found that the γδ T cells in meninges produced more IL-17 in response to the injection. When the animals were treated with antibiotics, however, the amount of IL-17 was reduced. The findings indicate that γδ T cells may sense the presence of normal bacteria, such as those that make up the gut microbiome, as well as invading bacterial species, and respond appropriately to regulate behavior.

The researchers speculate that the link between the immune system and the brain could have evolved as part of a multipronged survival strategy. “Our findings suggest that IL-17a production by meningeal γδ17 T cells represents an evolutionary bridge between this conserved anti-pathogen molecule and survival behavioral traits in vertebrates,” they wrote. “In the highly pathogenic ancestral environments, evolutionary conservation of tissue sentinels such as meningeal γδ17 T cells may have allowed organisms to respond rapidly to environmental stresses while also adapting to additional physiological processes, such as host alertness and exposure to external threats including predators and pathogens.”

In effect, increased alertness and vigilance could help rodents to survive an infection, by discouraging behaviors that increase the risk of further infection or predation while in a weakened state, suggested Alves de Lima. “The immune system and the brain have most likely co-evolved. Selecting special molecules to protect us immunologically and behaviorally at the same time is a smart way to protect against infection. This is a good example of how cytokines, which basically evolved to fight against pathogens, also are acting on the brain and modulating behavior.”

The researchers are now studying how γδ T cells in the meninges detect bacterial signals from other parts of the body. They also are investigating how IL-17 signaling in neurons translates into behavioral changes. “Our findings provide new insights into the neuroimmune interactions at the meningeal–brain interface and support further research into new therapies for neuropsychiatric conditions,” they suggested. “In the modern world, given the growing interest in the involvement of IL-17a in neuropsychiatric conditions such as anxiety, depression, and autism, our findings may shed new light on the understanding of these mechanisms and support further research on the development of new therapeutic targets.”

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