Studies Unmask Undercover Asthma Agent

Discovery of Link to Natural Killer T Cells Could Breathe Life into Search for a Cure

Asthma, the lung-choking disease that currently affects 17 million Americans, may turn out to have a surprising mastermind. Researchers have known for years that the symptoms of asthma—airway hyperreactivity and mucosal secretions—are the result of eosinophils, mast cells, and other immune cells acting under coordinated control. They thought this attack was orchestrated by type 2 helper (Th2) cells, detected in the airways of virtually all asthma patients. Yet Omid Akbari, Dale Umetsu, and their colleagues analyzed cells from the lungs of patients with moderate to severe asthma and found that more than half of what appear to be Th2 cells are not Th2 cells at all, but belong to an altogether different class—a subgroup of natural killer T cells. The findings appear in the March 16 New England Journal of Medicine.

Photo by Graham Ramsay

“We tell asthma patients that they need to be concerned about the proteins in their diet and that their disease has nothing to do with lipids or glycolipids. But that may, in fact, be wrong,” said Dale Umetsu (front), with Omid Akbari (left) and Everett Meyer.

In retrospect, it is easy to see why the culprits have escaped notice. On the surface, the newly identified natural killer T (NKT) cells resemble Th2 cells—both express the CD4 receptor and secrete the same cytokines. The NKT cells differ from Th2 cells nevertheless, but in ways that are entirely unexpected for an asthma-causing agent. What makes the discovery still more striking is that, in mice at least, the NKT cells appear to be even more powerful asthma agents than Th2 cells. Everett Meyer, Umetsu, and colleagues recently found that by activating these NKT cells, they were able to induce airway hyperreactivity in mice in the complete absence of Th2 cells. These findings appear in the Feb. 21 Proceedings of the National Academy of Sciences.

Taken together, the discoveries raise tantalizing questions—where do the NKT cells come from and how are they recruited to the lungs? How, exactly, are they activated and how do they summon other immune cells to carry out the actual work of inflammation? Akbari, HMS assistant professor of pediatrics; Umetsu, the Prince Turki Bin Abdul Aziz Al-Saud professor of pediatrics; and colleagues are currently trying to answer these questions. At the same time, the Children’s Hospital researchers are excited about the way the discovery addresses a long-standing clinical puzzle. Though physicians have successfully used corticosteroids to quell the symptoms of asthma, some patients simply do not respond. The question is: how might such patients be treated? The researchers believe that targeting the newly identified NKT cells might be an answer. “If we could develop future therapies that specifically target these NKT cells, we may be able to better treat patients with asthma, and in a much more specific fashion,” said Umetsu.

Lipid Allergens
There was probably little reason, in the 20 years since they were discovered, to suspect that NKT cells might play a critical role in asthma. For one thing, asthma is often associated with allergies to a wide range of antigens, such as those found in dust mites and pollen. Most T cells, including some NKT cells, carry a variety of T cell receptors (TCRs) to bind the wide range of antigens they may encounter, and one might expect this to be especially true of an asthma-causing agent. It turns out, the newly identified NKT cells belong to a subgroup of cells that carry a fixed TCR, hence their name, invariant NKT cells.

Nor do these invariant NKT cells interact with antigens in the expected way. Asthma is thought to be triggered by the protein portion of the allergen and, indeed, most T cells, including Th2, are activated by peptide antigens. These peptides are presented to them by the MHC class II complexes that sit on the surface of antigen-presenting cells. It turns out, invariant NKT cells do not even see peptides. Instead, their TCR is activated exclusively by glycolipids—presented not by MHC class II molecules but by the CD1d molecule, which is also found on the surface of some antigen-presenting cells. “These NKT cells respond to glycolipid antigens, which is totally new ground. People have not really suspected that lipids could be important in allergy,” said Umetsu.

Finally, it was thought that asthma, and indeed all allergies, entails a learning and memory experience on the part of the immune system. A T cell is taught which antigen to attack, sees that antigen, and only then undergoes an expansion in numbers. But invariant NKT cells are already expanded and poised for attack. In other words, they are members of the innate rather than the acquired immune system. “In the last five to eight years, there has been more interest in the innate system in almost every aspect of immunology, but not so much in allergy,” said Akbari. “With these NKT cells, we really have to start thinking much more about the innate immune system in allergy.”

Uncovering the Cause
What got longtime allergy researchers Umetsu and Akbari interested in NKT cells was the attention being paid to them in other areas of immunology, largely as a consequence of the cloning of the invariant TCR in the late 1990s. “I thought, well, maybe they’ll be important in asthma,” said Umetsu. The researchers began by trying to induce asthma, using a wide variety of agents, in a mouse knockout. “Lo and behold, we could not induce asthma in mice that lacked these NKT cells,” Umetsu said. “But if we gave back the NKT cells, the mice got full-blown asthma.”

NKT cells were clearly necessary for inducing asthma, but could they possibly be sufficient? Using a glycolipid antigen that activates invariant NKT cells directly, Meyer, a graduate student, Umetsu, Akbari, and colleagues, who were then at Stanford University, tried inducing asthma in mice lacking Th2 cells. As recently reported in PNAS, the mice developed airway hyperreactivity. While completing these experiments, the researchers wondered, could these NKT cells play a role in human asthma? They teamed up with Stanford pulmonologist John Faul, who collected cells from the lungs of 25 subjects, 14 with moderate to severe asthma, five with a different inflammatory lung disease, and six healthy controls. Though healthy subjects exhibited few immune cells of any kind, the two disease populations revealed high numbers of CD4-expressing cells. Akbari, Umetsu, and colleagues then analyzed the cells using a variety of methods, including invariant TCR–specific tetramers and antibodies, to see if NKT cells were present.

The results were striking. More than 60 percent of the CD4+ cells found in the lungs of asthmatic patients were NKT cells, not Th2 cells. This was true even of those who were being treated with corticosteroids, the main therapy for asthma. Intriguingly, the cells were not present in patients suffering from the other inflammatory lung disease, sarcoidosis.

The persistence of NKT cells even in treated asthma patients highlights a conundrum: there is no known cure for asthma. “We know how to treat the symptoms, we know how to reduce inflammation, but the reason we don’t have a cure is we do not know the final and basic mechanisms,” said Umetsu. “We would like to believe that NKT cells are the real cause of airway hyperreactivity asthma, but we need to do more experiments to substantiate this idea.”

He and Akbari do have an intriguing clue as to why the cells are such potent asthma-causing agents. “The amount of cytokine these cells can secrete in a short amount of time is enormous compared with Th2 cells,” Akbari said. “With their cytokines, they can toxify the lung in a very short time.” Clues like this could, eventually, lead to a way to eliminate disease.

“If we could find an antagonistic antigen—one that blocks the activation of NKT cells or makes them stop producing Th2 cytokines,” he said, “then potentially we could cure asthma.”

—Misia Landau

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