Shannon Turley, PhD

Answering one of the oldest questions in human physiology, researchers at Dana-Farber Cancer Institute have discovered why the body's immune system — perpetually on guard against foreign microbes like bacteria — doesn't attack tissues in the small intestine that harbor millions of bacteria cells.

In a study in the February issue of Nature Immunology, and which is currently available on the journal's Web site as an advanced online publication, investigators led by Shannon Turley, PhD, of Dana-Farber identify an unlikely group of peacemakers: lymph node cells that instruct key immune system cells to leave healthy tissue alone. The finding, which illuminates a previously unknown corner of the human immune system, may lead to new forms of treatment for autoimmune diseases such as Type 1 diabetes and multiple sclerosis.

"We've discovered that cells not generally thought of as part of the immune system actually play an important role in protecting the intestine from immune system attack," says Turley. "Because the cells are found in lymph nodes throughout the body, they may offer a way of suppressing a variety of autoimmune diseases," which result from immune system assault on healthy tissue.

The immune system distinguishes between normal and foreign agents by small proteins, called antigens, on the cell surface. In parts of the body, such as the pancreas, that are sheltered from the outside environment, cells known as dendritic cells display the antigens of their normal neighbors in a way that puts the immune system "at ease." By reading those antigens without being on alert, the immune system's T cells learn that such cells are off-limits to attack.

For years, scientists have wondered whether the same mechanism is at work in tissues that come in regular contact with bacteria and other microbial organisms. The small intestine, for example, which absorbs essential nutrients from food and drink and protects the body from invasive microbes, is literally teeming with bacteria, which help break down waste. The presence of so many bacteria is a potential trigger for an immune system response. Why do T cells almost always ignore the small intestine, leaving this vital tissue unharmed?

"It's obvious that T cells must be able to ignore — or become 'tolerized' to — normal intestinal tissue," states Turley, who is also an assistant professor of pathology at Harvard Medical School. "But it has been unclear how dendritic cells, which are extremely sensitive to microbial agents such as bacteria, teach T cells to resist attacking healthy intestinal cells."

In the new study, Turley and her colleagues found that, in fact, dendritic cells aren't essential in creating tolerance in T cells. Instead, and unexpectedly, tolerance is produced by "stromal" cells from nearby lymph nodes. Although they aren't classified as "professional antigen-presenters," as dendritic cells are, the stromal cells serve the same purpose: exhibiting normal-cell antigens to the immune system.

"Our study points to a previously unknown mechanism of immune system tolerance," Turley explains. "When you think of the conditions in the small intestine, with so many millions of bacteria cells and so much opportunity for dendritic cells to stimulate an immune attack, it's remarkable that intestinal tissue is so rarely the target of an immune attack. Our findings demonstrate that the immune system has features that remain to be discovered."

The study was funded by the Claudia Adams Barr Program for Innovative Cancer Research at Dana-Farber, the National Institute of Diabetes and Digestive Kidney Diseases, and the Institut de la Recherche Agronomique.

The lead author of the study is Je-Wook Lee, PhD, of Dana-Farber. Co-authors are Mathieu Epardaud, PhD, Jing Sun, MD, PhD, Jessica Becker, Alexander Cheng, and Ai-ris Yonekura, of Dana-Farber, and Joan Heath, PhD, of the Ludwig Institute for Cancer Research, Victoria, Australia.