Saving your self from yourself

“Your gut is a complicated place,” notes Shannon Turley, an assistant professor of pathology at Harvard Medical School. In addition to processing food three or more times a day, an intestine needs to protect you from being damaged by yourself.

For the food-processing task, your gut carries a small army of bacteria that turn steak and potatoes into tiny molecules your blood and gut can handle. But it also is continually tested with course after course of potentially dangerous molecules that cause a variety of ailments like inflammatory bowel disease. Turley and her colleagues are trying to find out how the gut manages to destroy these toxic molecules without harming “self,” normal tissues and organs, or the good bacteria that feed them.

In the process, they have discovered a new solution to this old puzzle, a solution that could lead to a novel way to treat self-attacking or autoimmune diseases. The same research may also shed light on why your body sometimes treats cancer tumors like steak and potatoes, or like normal parts of your body.

“We have found a new pathway that the body uses to establish and maintain tolerance of itself,” Turley says. “This finding involves cells not generally thought of as part of the body’s immune defense system, but they play an important role in educating that defense system.”

When germs enter your body, special cells quickly gobble up some of them, then chop their proteins into tiny pieces known as antigens. These antigen-presenting cells, as they are called, display any harmful molecules on their surfaces, like flags that warn, “this is not self.” (When cells are from normal organs, such as the kidney or liver, presenting cells then display “self” flags.)

White blood cells, called T cells, roam the body looking for such flags. These cells make up a powerful self-protecting army, wherein each soldier recognizes only specific “self flags,” like those from your gut or liver. When such encounters occur, a T cell continues on patrol without taking action. Non-self flags, on the other hand, trigger to a lethal attack on invading infections.

It’s a great system, honed over millions of years of evolution. But it’s not as simple as it might sound. In the small intestine, T cells encounter a multitude of different antigens, proteins from many sources. In addition to, say, salmonella bacteria, the gut teems with self-antigens, bacteria who work there, and, perhaps, bits of that chili dog you had for lunch.

How do T cells learn to attack the former and tolerate the latter?

When to kill

Until Turley and her colleagues, working at Dana-Farber Cancer Institute in Boston, did their investigation, it was believed that T cells are educated for tolerance only in the thymus, a gland in the upper chest behind the breastbone. The thymus is a kind of data center where files on self-antigens from every part of the body are kept. It is here, and only here, that T cells are taught to recognize self-antigens that must be tolerated, it was widely believed.

But Turley and her team found tolerance is also produced in lymph nodes. These nodes occur at the intersection of vessels that contain antigens floating in a fluid (lymph), and blood vessels that carry T-cells. The finding that tolerance is taught in this intricate network as well as in the thymus means that cells can be educated all over the body, wherever lymph and T cells come together.

“Our results point to a previously unknown mechanism of immune system tolerance,” Turley explains. “When you think of conditions in the small intestine, with many millions of bacteria cells and so much opportunity to launch an immune attack, it’s remarkable that intestinal tissue is so rarely attacked. These findings demonstrate that the immune system has features yet to be discovered.”

Turley’s team describes this work in the February issue of Nature Immunology. Lead author of the report is Je-Wook Lee, formerly a research fellow at Harvard Medical School.

When not to kill

Being able to better tune the body’s defenses offers the possibility of a wide range of novel therapies to treat diseases like arthritis and diabetes, to combat transplant rejection, and, perhaps, to fight cancer.

“We’re working very hard right now to see if we can exploit the functions of lymph nodes to treat autoimmune diseases,” Turley explains. In such diseases, T cells attack the self, rather than the non-self. Assaults on organs such as the pancreas lead to type 1 diabetes. More widely spread self-strikes cause rheumatoid arthritis, lupus, and multiple sclerosis. “We may be able to present antigens we want in ways that we want to suppress or prevent attacks of specific organs or tissues,” Turley says.

When people receive transplanted kidneys, livers, or other organs, they must take anti-rejection drugs to block killer T cells, which normally blitz such non-self parts. Turley sees a possibility of mobilizing lymph nodes to suppress rejection of non-self parts that people want to be part of self.

Another intriguing possibility involves using lymph cells to fight what may be tolerance to cancer tumors. “Tolerance to such tumors might, at least partially, explain why the body does not always launch successful attacks against them,” Turley speculates. “We have just begun to think that cancer cells may be able to express antigens that might promote their acceptance. If so, we want to find ways to suppress this tolerance of tumors.”