STANFORD, Calif. – For the second time in two years, scientists at the Stanford University School of Medicine have discovered a new type of regulatory T cell that reduces asthma and airway inflammation in mice, bolstering the theory that a deficiency of such cells is a prime cause of the breathing disorder as well as allergies.
The team's research not only provides a detailed profile of these newfound cells but also sheds light on how such cells are related to other T cells and suggests that there exists a spectrum of regulatory T cells, known as Tregs, to be identified and studied.
"It's likely that Tregs aren't functioning or developing properly in people who suffer from asthma and allergies," said Dale Umetsu, MD, PhD, professor of pediatrics who led the research team. "This new understanding of the fine characteristics of regulatory T cells brings us closer to developing therapies that will provide cures for allergies, asthma and perhaps a number of other diseases involving immune dysregulation," added Umetsu, who is also chief of the division of allergy and immunology at Lucile Packard Children's Hospital at Stanford.
Humans have a variety of T cells – including regulatory (Tregs), helper (Th) and natural killer (NKTs) – and there are different types within each of those categories. But all of them play a critical role in how, ideally, the human immune system responds when invaded by viruses, bacteria and allergens: the cells fight the enemies – the viruses and bacteria – and ignore the innocuous visitors – the allergens. The problem for allergy and asthma sufferers is that the body responds to allergens as if they were reviled foes, engaging in a full-out battle that inflames airways and impedes breathing.
In hopes of preventing such reactions, the Stanford researchers have been studying the Tregs, which appear to act as the immune system's peacekeepers, signaling to other T cells when to hold off from attacking an intruder. Two years ago, they identified one type of Treg cell that could reduce airway inflammation and asthma in mice. And now, in a study published in the Sept. 26 online version of Nature Immunology, they have identified another type of regulatory T cell that produced the same result: the airways of mice that received injections of the cells were not inflamed despite confrontation with allergens.
The team's findings also show that all of the Tregs share important features that might explain how they exert a calming influence on their battle-hungry brethren. Before now, researchers had identified two broad categories of Tregs – natural and adaptive. Natural Tregs are produced in the thymus, are always present in predictable quantities and appear to be important in the prevention of autoimmune disease. Adaptive regulatory T cells, the type studied by Umetsu and his colleagues, develop in response to incoming invaders and have been thought to be quite distinct from natural Tregs.
But Umetsu and his colleagues found that both the adaptive and natural Tregs depend on a gene called Foxp3. When this gene doesn't function properly in humans, they lack natural Tregs and develop an autoimmune disorder called IPEX Syndrome, which includes severe allergies among its symptoms. By identifying this gene in the adaptive Tregs, the researchers add credence to the idea that nonfunctional or inadequate Tregs lead to allergies.
The researchers also found that the two adaptive Tregs share certain characteristics. Both appear to communicate their peacekeeping message using the same language: they produce a chemical called IL-10 and signal their desires through the same pipeline, known as the ICOS-ICOSL regulatory pathway.
But the two types of Tregs exhibit intriguing differences. Umetsu said each appears to be associated with a different helper T cell (Th cell). Each Treg has a gene turned on that is also turned on in the corresponding Th cell, and each Treg appears to be produced in greater numbers when its corresponding Th cell responds to an intruder. Although an excess of one of the Th cells is associated with autoimmune diseases such as multiple sclerosis and type 1-diabetes, and an excess of the other is linked to allergies and asthma, both Th cells cause inflammation. In turn, the two Treg cells have the opposite effect. "Both can help reduce airway inflammation," said Umetsu.
"We have now found several subtypes of regulatory T cells," he added, "and we are proposing how these are all interrelated. We believe this study provides a scaffold for future studies of regulatory T cells."
Umetsu's Stanford collaborators include Philippe Stock, MD, PhD; Omid Akbari, PhD; Rosemarie DeKruyff, PhD, professor of pediatrics; and Gerald Berry, MD, associate professor of pathology.
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