Unsung Heroes: Are immune cells protecting us from more than just pathogens?

Interactions between the brain and the immune system have been in the news a lot recently with recent concerns about the impacts of COVID-19 on the nervous system. The brain has largely been considered an immune-privileged organ, meaning that immune cells from other parts of the body are not thought to be able to enter it. However, this initial assumption has been challenged by what is now a growing number of studies.

A recent study by Kalil Alves de Lima and others in the laboratories of Dr. Jasmin Herz and Dr. Jonathan Kipnis at Washington University of St. Louis has explored what happens when immune cells come in close contact with the brain. Their study shows that a particular subset of immune cells releases a signal that can cause anxiety-like behavior in mice, an impact that could be seen as a secondary protective role of immune cells, protecting mice from potential threats in the environment.

The Kipnis lab has led the paradigm shift in how we think about interactions between the brain and the immune system. The lab was the first to report that vessels in the layers of the protective membrane that cover the brain, the meninges, directly linked the brain and the lymphatic system, a network of tissues and organs that contain lymph, a fluid filled with infection-fighting immune cells. They’ve also found new roles that immune cells play, including in spatial learning and pro-social behaviors.

Fig 1. γδ-T-cell-deficient mice (Tcrd-/-) show more exploration of open unprotected areas in the elevated plus maze (a) and open field task (b), indicating lower anxiety.

In this study, researchers in the Kipnis lab sought to further characterize the population of immune cells that reside in the meninges. They isolated an outermost layer of this tissue, called the dura, and analyzed the cell types it was composed of. They saw that a known population of T cells, called γδ T cells because they express a special T cell receptor of the γδ type, are abundant in the dura of these mice. These cells are a subclass of γδ T cells that produces a molecule called interleukin-17a (IL-17a). IL-17a is a member of a class of molecules that are used by the immune system to do things such as recruit other immune cells to the site of inflammation. The authors wondered: why would these cells be enriched in this area and why would there exist a source of IL-17a so close to the brain?

When and how does this population of cells accumulate in the dural meninges? The authors found that these γδ T cells are not present before birth, but by seven days post-birth are quite substantial in number, suggesting that they begin to accumulate in early life. To better understand where these cells come from, the authors performed an experiment for figuring out whether an immune cell type is the kind to circulate through a bunch of tissues or if it is tissue-resident (remains in a particular tissue and does not circulate and surveil other tissues). This experiment involves connecting the circulatory system of two mice that differ in one place in their genome, waiting a bit, and then checking the immune cells in an area for their genetic identity to see if they are from the host animal (suggesting they are tissue-resident) or from the other animal (suggesting they are circulating). They saw that almost all of the γδ T cells in the dural meninges are tissue-resident, indicating that there might be a special need for these IL-17a-producing cells so close to the brain. As for what signals cause these cells to accumulate in and stay in the dural meninges, the authors suggest that a molecule called CXCL6 may be responsible for “calling” the cells to the tissue, as these cells have the receptor for CXCL6 that allows them to recognize it. 

Curious about whether having a population of immune cells in close proximity to the brain might have an impact on healthy brain function, the authors tested mice that lacked these γδ T cells on behavioral tasks. They found that the mice spent a lot of time exploring open unprotected areas on two behavioral tasks called the elevated plus maze and open field task. Think about what this might mean for a mouse in the wild-- if they spent more time exploring unprotected areas, what kind of threats might they encounter? These mice are not avoiding threats as they normally would or should. The authors also targeted γδ T cells in otherwise normal mice using antibodies, and this showed similar results. As this use of antibodies to target the cells led to reduced levels of IL-17a, they suspected IL-17a might be linked to the anxiety-like behavior. They then injected IL-17a into otherwise IL-17a-deficient mice that lacked γδ T cells and found increased anxiety-like behaviors.

How might a finding like this be relevant in humans? Humans don’t face the same kinds of environmental threats as do mice and other animals, so how might we interpret the impact of IL-17a on people? Anxiety disorders are one of the most common categories of mental disorders worldwide. A common behavioral feature of anxiety disorders is excessive avoidance of perceived external threats. For example, specific phobias like claustrophobia or arachnophobia, are a subcategory of anxiety disorder involving the irrational fear of a specific trigger that can lead to the avoidance of that trigger. Now, at some point in evolution we did have more threats in our environment, so it was important for us to develop these kinds of anxiety-like or threat-avoidance behaviors in response to real threats, but now it is not uncommon for people to experience anxiety-like or threat-avoidance behaviors in response to perceived threats. Many people decide to undergo treatment for their anxiety disorders, which can involve exposure-based or medication-based therapy.

This begs the question: if IL-17a-mediated anxiety is a thing in humans, how might it be acting on circuits in the brain, and could we use this knowledge to treat it? In order to figure this out, the authors first needed to look into how IL-17a is impacting neuronal function. They found that a receptor subunit for IL-17a, IL-17Ra, was expressed in neurons of circuits in the brain involved in response to threat. This suggests that IL-17a directly signals to neurons to impact these anxiety behaviors, and not through secondary means. They then looked at the genes that were affected in these brain circuits, in the absence of IL-17a, and of note they found that genes were upregulated in a pathway that is a target of anti-anxiety drugs. To me, this suggests a clear direct link between IL-17a and increased anxiety-like behaviors and avoidance of threat, but also that if there is a way to reduce IL-17a, it can potentially have an impact not too dissimilar from that of anti-anxiety medications that are regularly used to treat anxiety in humans. 

These findings, together, change the way we think about how our immune system interacts with our nervous system. It seems as though neuroimmune interactions exist not just to protect us from pathogenic threats, but also to stimulate other pro-survival functions such as threat avoidance by directly signaling to neurons. It would be cool to know in what other ways these immune cell “soldiers” protect us by influencing our behaviors.

Edited by Arielle Keller

Article: Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons by Alves de Lima et al (2020) Nature Immunology