Jonathan Kipnis, a neuroimmunologist in the University of Virginia School of Medicine’s department of neuroscience, has discovered a possible link, a modern twist on the age-old notion of the body-mind connection. His research suggests that the immune system engages the brain in an intricate dialogue that can influence our thought processes, coaxing our brains to work at their best.
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Kipnis got the idea of an immunity-intelligence link while earning his Ph.D. at the Weizmann Institute of Science in Israel. His adviser, Michal Schwartz, was performing experiments to understand how the brain repairs itself after an injury. She found that the brain depends on a type of immune cell known as the T cell, which normally kills infected cells or leads other immune cells in a campaign against foreign invaders. Her research suggested that T cells can also send signals that activate the brain’s resident immune cells, microglia and blood-borne macrophages, telling them to protect the injured neurons from toxins released by the injury.
Without T cells, Schwartz and other researchers have found, the brain does a bad job of healing itself. Kipnis was fascinated by the discovery because he knew that T cells cannot get past the blood-brain barrier. Yet apparently they could significantly influence the brain from a distance. He wondered if T cells did more for the brain than just help heal wounds. “The crazy idea came to me: What if we needed T cells for healthy brain function?” Kipnis says.
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Because the blood-brain barrier made it impossible for the T cells to affect the brain from the inside, Kipnis wondered whether they were maximizing their long-distance influence by getting as close as they could to the brain.
It has long been known that the membranes encasing the brain, called the meninges, are loaded with T cells and other immune cells. Kipnis and his colleagues wondered how smart mice would be if they had a normal supply of T cells everywhere in their bodies except the meninges, so he injected a compound into mice that prevented T cells from reaching the meninges. When those animals were put into a water maze, they, too, performed badly—just as Kipnis had predicted.
Guarding the Brain
Kipnis is now investigating what exactly the T cells surrounding the brain are doing to make the brain work well. One strong possibility: They keep the rest of the immune system from inadvertently harming it.
When we learn something new, our neurons tear down old connections and build new ones. In the process they cast off lots of molecules. To the immune system, this waste may look like an infection or some other kind of trouble, resulting in inflammation and the release of harsh compounds that normally fight viruses but can also interfere with the brain and its function.
Kipnis suggests that T cells keep this process in check, differentiating between disease and ordinary stress and, when warranted, telling other immune cells to stand down by releasing antagonist molecules that prevent misguided inflammation.
The same T cells that protect the brain from inflammation also work to keep us sharp; and in what appears to be a feedback loop, the mere act of learning reinforces the effect [of learning, of being sharp mentally]:
As mice learn something new, T cells in the meninges produce high levels of...interleukin 4 (IL-4)...an immune system signal that curbs the inflammatory response and also improves learning.
Indeed, when mice lacking the gene for making IL-4 take the water maze test, they do badly, perhaps because their T cells lack a critical signal involved in fast learning.
This theory could explain why we lose our mental edge when we get sick, Kipnis says. When we’re healthy, T cells keep the immune cells in the meninges from inflaming the brain. But when we get sick, the T cells loosen their hold to let the immune system attack invading pathogens. The resulting inflammation helps clear out the invaders, but it also blunts learning. When we’re sick, Kipnis proposes, it’s more important to launch a powerful immune attack than to have a sharp mind. “Everything in life is priorities,” he says.
Kipnis has recently started to investigate what happens to people’s brains when they start losing T cells. People with cancer, for example, often suffer a loss of T cells when they undergo chemotherapy. It may be no coincidence, he argues, that chemotherapy is notorious for causing “chemo brain”—a fuzzy mental state in which patients have trouble thinking clearly. Kipnis proposes that without T cells to keep inflammation in check, immune cells in the meninges pump harmful compounds into the brain.
