Survival of the Fretful: The Link Between Immune Cells and Anxiety

Picture your typical horror movie. The eerie music starts to build as the antagonist rounds the corner. With ice in their veins and a chill down their spine, the unknowing protagonist becomes hyper-aware of their surroundings and is quick to react – doing anything they can to survive the oncoming threat. This character exhibits what we call anxiety-like behaviors, which aid in survival by increasing alertness and reaction speed to different stimuli.

A recent study by Alves de Lima and colleagues has identified a subpopulation of fundamental immune cells, T cells, that may mediate such behaviors in mice. This evidence provides an avenue to explore the link between neuropsychiatric conditions and immunology to further our understanding and potentially develop novel therapeutics.

The Brains Behind Behavior 

The brain itself is an incredibly complex organ of the central nervous system (CNS) with many layers to understand – literally! Necessary for protecting this vital organ, the meninges are layers of tissue that surround the brain. In recent years, meningeal immunity has been of great interest as the meningeal layers contain a rich immune network not yet fully explored; therefore, further research may help scientists finally unveil the link between the brain and the immune system. Implicated in this fascinating relationship are the chemical messengers of immunity: cytokines. These proteins can be detected and bound by nearby cells. This interaction tells the cells to make other proteins needed to induce a specific response against problems like an infection or injury. Strong evidence suggests that meningeal immune cells and the cytokines they produce can affect different brain functions like sociability, learning, and memory

The immune system is an intricate mosaic made of many different parts. One critical aspect of the immune system is the aforementioned T cell. Depending on the specific subset, these cells are responsible for recognizing bacteria or viruses that enter the body, activating other immune-associated components, and killing infected cells. We can categorize T cells based on the type of molecule expressed on the cell’s surface, like receptors that can bind to a specific entity. The γδ T cell receptor characterizes a rare subpopulation of immune cells, appropriately known as γδ T cells, enriched in areas like the meninges. They produce essential cytokines like IL-17a implicated in meningeal immunity. It follows that understanding γδ T cells may provide further insight into the link between the brain and the immune system.

By studying mice, scientists have identified meningeal γδ T cells defined by two key features: the chemokine receptor CXCR6 and the transcription factor RORγt. Chemokines are a specific subset of cytokines that recruit immune cells to a particular spot. Accordingly, CXCR6 is a receptor that binds chemokines and may be important in recruiting γδ T cells into the meninges for closer proximity to the CNS. On the other hand, transcription factors are proteins that bind to a particular DNA sequence to control whether a gene is “on” or “off.” RORγt, in particular, is believed to be essential for the secretion of the cytokine IL-17a. 

So what’s the big deal with these discoveries?

Well, the bulk of cells that make up the CNS, neurons, have been found to express receptors that can bind IL-17a. Given that γδ T cells can be recruited into the meninges and can produce IL-17a cytokines, this neuronal expression strongly suggests that IL-17a may have some form of control over brain functions like behavior!

Figure 1: Meningeal Immune Cell Signaling on Behavior. a) Meningeal γδ T cells produce IL-17a cytokines that impact mice behaviors. b) This occurs via IL-17a binding to IL-17a receptors on neurons. Triggering these anxiety-like behaviors is important for survival because it induces increased alertness and vigilance as well as reaction speed. Figure created with BioRender.com.

Of Mice and Men-ingeal IL-17a-secreting T cells 

To investigate the relationship between meningeal γδ T cells, IL-17a, and anxiety-like behaviors in mice, Alves de Lima et al. explored what would happen with the loss of both γδ T cells and IL-17a. In particular, they observed any changes in mice through a series of behavioral tests.

The two behavioral tests used in this study were the elevated plus maze and open field tests. On the one hand, the elevated plus maze test is a standard tool to measure anxiety-like behavior in laboratory animals. The apparatus used is set up to have perpendicular lanes – with one wide-open and the other enclosed – that resemble a plus sign. The expected behavior was for mice to avoid the open, unprotected lanes and remain only within the enclosed areas. Such actions signify increased avoidance and fear of potential environmental threats. While this was true for the control mice, the mice lacking γδ T cells showed significantly increased exploration time in the open arms. These observations allude to decreased anxiety-like behavior with the loss of γδ T cells. This test was repeated using mice lacking IL-17a. All cases yielded very similar results, further cementing the role of γδ T cells and IL-17a in regulating anxiety-like behavior. 

The second test used was the open field test. Like the elevated plus maze test, the expected behavior was for mice to explore the peripheries while avoiding the enclosure’s center. These actions coincide with increased vigilance of the environment in which there are no enclosed areas; thus, increased vigilance denotes anxiety-like behavior. Comparing the control versus mice lacking γδ T cells showed that the latter cohort spent more time in the center than the former. Alongside the previous behavioral test, the results suggest a proportional relationship between γδ T cells, IL-17a and the survival instincts of anxiety-like behavior. 

Figure 2: Anxiety-like behavior experiments. Observing presence or decrease of anxiety-like behavior in the elevated plus maze test and open field test of a) control mice and b) mice lacking γδ T cells and IL-17a, respectively. Figure created with BioRender.com.

In summary, the loss of γδ T cell and IL-17a coincides with decreased anxiety-like behavior and vice versa. Although such findings were studied in mice, this discovery hints at further avenues of exploration to develop new understandings of anxiety in humans. Overall, these general findings may indicate the importance of IL-17a as a therapeutic target for anxiety disorders. 

Though further work is required to solve the mysteries surrounding the brain and immune system, particularly research more generalizable to humans, this exciting finding is undoubtedly a step forward. For any unfortunate horror movie character, perhaps a healthy dose of fear is necessary to drive survival instinct. To some degree, the immune system may be the critical factor that drives this fear-induced survival!

 

 

Journal Article: Alves de Lima, K., Rustenhoven, J., Da Mesquita, S., Wall, M., Salvador, A.F., Smirnov, I. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol 21, 1421-1429 (2020). https://doi.org/10.1038/s41590-020-0776-4

Cover Image: Signaling in Neurons by National Institutes of Health, CC BY-NC 2.0 

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