Science Editor

Most of the attention to the link between the immune system and cognitive abilities has been on the problems the former can cause for the latter. Inflammation is a culprit in brain disorders such as Alzheimer's disease.

But new studies, published in the May 3, 2010, issue of the Journal of Experimental Medicine showed that some workings of the immune system can be helpful for learning as well. Specifically, in animal studies, T cells and the cytokine interleukin-4 they secreted were important during maze learning.

Senior author Jonathan Kipnis, an assistant professor of neuroscience at the University of Virginia, began to look at the relationship between the immune system and the brain, basically on a hunch.

The widespread view at the time was that the brain and the immune system were separated by an impenetrable wall.

But "the immune system patrols the CNS," Kipnis told BioWorld Today. "The cells don't go inside the brain, but they are almost there" - in the meninges, several layers of cells that line the brain and provide support and protection.

The brain, in turn, "has learned to live with the immune system in those areas." And given that biology tends to make use of whatever is around, Kipnis reasoned that the T cells might influence the brain, and phenomena like HIV dementia or the cognitive effects of cancer treatment that is sometimes called chemo brain "could be due to [effects on] meningeal immunity."

In their paper, Kipnis and his team first treated mice with an immunosuppressant drug that sequesters T cells, and found that a week of such treatment gave them memory deficits when they learned how to get around a maze. Treatment with a more specific antibody that prevented T cells from going into the meninges led to the same learning defects.

The T cells do not interact with neurons directly - in fact, they are prevented from any such interactions by the blood-brain barrier, and the meninges are a neuron-free zone. Instead, they secrete a cytokine, interleukin-4, that is critical for their effects.

When Kipnis and his team tested IL-4 knockout animals, they also had memory deficits; bone marrow transplantation experiments revealed that it was specifically interleukin-4 in the immune system that was important for normal learning to occur.

Interleukin-4, Kipnis said, works in "at least two" ways. First, the T cells regulate another immune cell type, meningeal myeloid cells.

When T cells are absent, the myeloid cells will develop "a severe proinflammatory phenotype," Kipnis said.

The interleukin-4 secreted by the T cells appears to shut down the myeloid production of proinflammatory cytokines.

Interleukin-4 also crosses into the brain - either by diffusion across the innermost meningeal layer, or through as-yet unidentified transporters. And once it does, it induces a type of brain support cell known as astrocytes to secrete brain-derived neurotrophic factor, or BDNF - a factor known to play a role in brain plasticity and memory formation.

Though the work is currently at its earliest stages, "the potential practical applications are huge," Kipnis said.

He believes the most promising strategy is most likely not to target T cells directly, given that T-cell reduction is inevitable both in diseases like HIV dementia and treatments like chemotherapy. Instead, he said, the goal should most likely be to "mimic what T cells do without actually boosting T cells," perhaps by administering interleukin-4 therapeutically, or targeting myeloid cells in vitro.

And on the most basic level, Kipnis said, the work suggested that a re-evaluation of the interactions of the nervous system and the immune system are in order.

"For so many years," he said, "it was thought that if you see T cells in the brain, that's a bad thing. What we show is that no, it can be good."