Mobilizing the immune system’s ‘natural killers’ against inflammatory bowel disease

Stripped of their STAT1 protein “shield,” the helper T cells that cause inflammatory
bowel disease are wiped out by the immune system’s “natural killer” (NK) cells.

The human immune system includes about a dozen major cell types with specialized roles in the body’s defenses. They serve as sentries, identify threats, mobilize troops, capture and transport invaders, interrogate and kill those deemed dangerous and clear the battlefield of casualties. This intricate command-and-control system is what enables us to fend off most of the dangerous bacteria and viruses that come our way.

But in patients who suffer from inflammatory bowel disease (IBD), the immune system itself becomes the enemy. Even when the body faces no threat, immune cells called “helper T cells” take up arms, resulting in a kind of perpetual warfare that — far from being helpful — causes collateral damage to the gut.

“The system goes into overdrive,” says Yu Hui Kang, an immunology graduate student at Harvard Medical School and a researcher at Boston Children’s Hospital. “These cells have gone too far, and they can’t stop.”

Now Kang and colleagues in the lab of Scott Snapper, MD, PhD, director of Boston Children’s Inflammatory Bowel Disease Center, may have found a way to turn the tables on the immune system by recruiting its own “natural killer” cells to wipe out the harmful T cells. Though clinical applications are years away, the work suggests new avenues for developing treatments for the debilitating disease.

Fighting imaginary enemies

IBD (not to be confused with irritable bowel syndrome), includes two distinct conditions: ulcerative colitis and Crohn’s disease. Together they affect about 1.6 million Americans, including 80,000 children, causing abdominal pain, persistent diarrhea, rectal bleeding, weight loss and fatigue.

These painful symptoms are the result of an immune system gone awry — mustering an attack when it’s not needed. One area of the body where this can happen is the gut, which is teeming with bacteria, viruses and other microorganisms. Many of these microbes are actually helpful to us, and in healthy people the immune system recognizes that and lets the “microbiota” be. But in people with IBD, the “helper” T cells keep fighting imaginary enemies, resulting in chronic inflammation.

Jamming the T cell’s communication system

One recent ray of hope for IBD sufferers is the drug tofacitinib, approved by the FDA in 2018 for treatment of ulcerative colitis. Now in clinical trials for treatment of Crohn’s disease, “tofa” works in part by jamming a key part of the T cells’ internal communication system, known as the JAK-STAT pathway. “It shuts the pathway down,” Kang says.

Seeking a more targeted approach with potentially fewer side effects, Kang focused on a single messenger in that pathway — a protein called STAT1, which has been associated with Crohn’s disease. His experiments, described in a paper published in February in Nature Communications, reveal an unexpected ally in the fight against inflammation.

The system goes into overdrive. These cells have gone too far, and they can’t stop.”

Working with mice that had an IBD-like disease, Kang knocked out the gene for STAT1 in the helper T cells and then watched to see what happened to them in the gut.

“What I found was that when you get rid of the STAT1 gene, the helper cells actually get killed by the natural killer cells,” he says. “When these T cells are killed, they no longer cause the disease.”

Removing the shield against friendly fire

Natural killer (NK) cells are a vital part of the immune system, patrolling the body in search of potential threats. “If you have a cell that’s been infected by a virus, or has become a tumor, the natural killer cells can recognize that and kill it,” Kang says.

natural killer cells can be mobilized against inflammatory bowel disease
Electron micrograph of natural killer cell (IMAGE: WIKIMEDIA COMMONS)

But NK cells normally hold their fire against other cells in the immune system. The fact that they turned on T cells lacking STAT1 suggests that one of the protein’s roles is to serve as a kind of shield against “friendly fire” from NK cells. Removing the STAT1 gene marks the helper T cells as “harmful” to the body and unleashes NK cells to wipe them out.

Of course, a treatment that wiped out all the body’s helper T cells would do more harm than good, since they perform many useful functions in the immune system. But Kang found that the NK cells targeted only those STAT1-deprived T cells that were reacting to the microbiota of the gut. That suggests that targeting the STAT1 gene may be a fruitful approach for developing new treatments for IBD.

Another potential approach is to explore other ways to selectively harness the NK cells’ ability to kill “harmful” immune cells. “We can now study this cell type and investigate its ability to suppress IBD in general,” Kang says. “That’s an area that we’re pretty interested in — whether we can use this particular cell type as a therapeutic option for this disease.”

Amlan Biswas and Michael Field, both of the Division of Gastroenterology, Hepatology and Nutrition at Boston Children’s Hospital, were co-authors on the paper. The study was supported by the National Institutes of Health, an A*STAR National Science Scholarship (Singapore), a CCFA Career Development Award, the Helmsley Charitable Trust, and the Wolpow Family Chair in IBD Treatment and Research.

More on research in the Snapper lab.