T Cells Take Up Residence in the Healthy Brain Via a Gut-Fat-Brain Axis

The brain is a unique place. It is shielded from much of the body by the blood-brain barrier, meaning it’s protected from pathogens and potentially dangerous substances that might be in our blood. And historically, many scientists believed that separation extended to the immune system as well: The brain has its own specialized immune cells called microglia, but immune cells present in the rest of the body were long thought to steer clear of the brain unless there was a disease or other problem requiring their presence.

Now, a team of scientists from Yale School of Medicine (YSM) has shown that immune cells known as T cells reside in the healthy brains of mice and humans, trafficked there from the gut and fat. This is the first time T cells have been shown to inhabit the brain under normal, non-diseased conditions.

The findings were published May 28 in Nature.

The presence of T cells in the healthy brain and evidence that they travel between the brain and other parts of the body upend the field’s dogma about the role of T cells in the brain, the study authors say. Pathologists have seen T cells in the brain before, but it was assumed they were there responding to current or previous infections.

“We think of T cells as something that fights off infection and causes autoimmune disease, but the surprise of this study is that T cells have a different role in biology that we were unaware of,” says David Hafler, MD, William S. and Lois Stiles Edgerly Professor of Neurology at YSM. “With this paper, we’ve definitively shown that their presence is not just disease-related but part of normal physiology, and that changes everything.”

The researchers found T cells most densely concentrated in a small region called the subfornical organ, which is nestled deep inside the brain and is known to regulate thirst and hunger. The team found the cells in the subfornical organs of laboratory mice and of people who had died and donated their brains to science. This part of the brain also has a slightly leaky blood-brain-barrier, which researchers believe allows cells in this brain region to more readily receive signals from the blood to know when its host animal needs to drink or eat.

“This makes it all the more interesting that immune cells are also there, presumably to provide some kind of signal about the body’s normal state,” says Tomomi Yoshida, a YSM doctoral student and first author of the study. Yoshida led the work along with Andrew Wang, MD, PhD, associate professor of internal medicine and immunobiology, and Hafler.

T cells perform many different functions, and researchers often categorize this broad class of immune cells into finer subclasses based on the kinds of proteins they display on their surfaces. Looking at the brain’s T cells through this lens, the YSM researchers found that they were different from the T cells present in the membrane that surrounds the brain and were most similar to those that reside in the gut and fat tissue.

In mice, altering the gut microbiome affected the transport of these T cells to the brain. The researchers found that when baby mice weaned and started on solid food, the corresponding shift in their gut microbiomes kicked off T cells’ travel from gut to brain. Mice reared in a germ-free environment, with no gut microbiomes, didn’t have T cells in their brains. And depleting the animals of the brain T cells changed their food-seeking behavior when the mice were offered food following a short fast.

The researchers believe that the immune cells may be signaling the status of the body to the brain through a previously undiscovered form of gut-brain communication. The highway of information between the digestive system and the brain, also called the gut-brain axis, plays many important roles in our health and well-being, but previous studies had not uncovered a direct route for immune cells to enter the brain from the gut.

Other means of gut-brain communication include the vagus nerve, which directly connects the brain to the intestines, and small molecules secreted into the blood. Relying on the diffusion of molecules in the blood struck Wang as an inefficient method of communication.

“From a design principle, it seems kind of a risky way to send information,” he says. “How cool would it be if you actually reprogrammed an immune cell to represent the state of the gut and you then send that cell to the brain, where it can tell the brain what it saw and allow the brain to adapt based on that information?”

That’s exactly what Wang and his colleagues think is happening. The T cells could be telling the brain about the body’s nutrition status, but they could also be conveying other important signals such as the state of the gut microbiome, the researchers hypothesize. Wang believes they might be stopping in fat tissue on their way from the gut to the brain as a sort of quality-control checkpoint, but that remains to be tested.

The scientists next want to look at how the T cells know to move from the gut to the brain as well as what happens to these cells in neurological diseases such as multiple sclerosis or Parkinson’s disease.

“This study raises more questions than it answers,” says Yoshida. “But they’re all interesting questions.”

The research reported in this news article was supported by the National Institutes of Health (awards R01AI162645, R01AR080104, P01AI073748, R01AI22220, UM1HG009390, P01AI039671, P50CA121974, R01CA227473, 1F31NS130957-01A1, DP1DA050986, and R37AR40072) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research was also supported by the Smith Family Foundation, the Colton Center for Autoimmunity at Yale, the Food and Allergy Science Initiative, the PEW Charitable Trusts, the Mathers Family Foundation, the Ludwig Family Foundation, the Knights of Columbus, Race to Erase MS, the Chan Zuckerberg Initiative and the National MS Society.