Why TH17 Cells Turn to the Dark Side

Whenever a criminal gets arrested, everyone asks why he went bad. Was it his upbringing? Did he fall under the influence of the wrong crowd? Did he watch too many episodes of The Sopranos? Researchers have been asking similar questions about TH17 cells, helper T cells that foster autoimmune diseases, including possibly MS, but that are also crucial for combating pathogens. Now, a new study pinpoints a protein that steers the cells down the wrong path.

“I think this is a valuable contribution,” says neuroimmunologist Benjamin Segal of the University of Michigan Medical School in Ann Arbor, who wasn’t involved in the work. “It adds another element to our understanding of what makes a myelin-reactive T cell pathogenic.” Immunologist Vijay Kuchroo of Harvard Medical School in Boston, Massachusetts, and colleagues reported the findings online last week in Nature Immunology (Lee et al., 2012).

The interplay among the cytokines that an immune cell encounters and produces itself is the key to adjusting its behavior. TH17 cells—so named because they emit the inflammation-stimulating cytokine IL-17—have earned a reputation as fierce promoters of autoimmunity. Studies suggest that the cells orchestrate inflammation in diseases such as psoriasis, inflammatory bowel disease, and rheumatoid arthritis. TH17 cells also trigger nerve damage in experimental autoimmune encephalomyelitis (EAE; see Animal Arsenal), and brain lesions of MS patients produce high levels of IL-17 (Lock et al., 2002). Despite suggestions that TH17 cells contribute to MS, studies haven’t confirmed their guilt.

Studies from the past few years indicate that the cells have a split personality, however. “These cells didn’t evolve to induce autoimmunity,” Kuchroo says. “Their main job is to clear infections.” For example, other researchers have revealed that some TH17 cells specialize to battle either harmful fungi or pathogenic bacteria that invade our bodies (Zielinski et al., 2012). In addition, the cells might have a softer side. TH17 cells that dwell in the intestines seem to mellow, gaining the ability to quell immune attacks (Esplugues et al., 2011).

The question, then, is what determines a TH17 cell’s character. Researchers have begun to delineate which combination of cytokines turns a TH17 cell to the dark side. These studies have found that IL-6 and TGF-β1 stimulate immature CD4 cells to specialize into TH17 cells, but the cells don’t become destructive until they are bathed in IL-23.  

Kuchroo and colleagues refined the recipe for making a bad TH17 cell. The researchers found that IL-23 spurs TH17 cells to manufacture TGF-β3, a relative of TGF-β1. The TGF-β3 that a TH17 cell produces could unleash its sinister side—or could even spread and have a bad influence on neighboring cells. To test that idea, the team dosed immature T cells with IL-6 and either TGF-β1 or TGF-β3, and then infused the resulting cells into mice. The combination of TGF-β3 and IL-6 spurred the cells to mature into TH17 cells, but it led them astray. Rodents developed severe EAE if they received cells that had been marinated in this combination, the researchers found, whereas mice that received TH17 cells stimulated with IL-6 and TGF-β1 showed only mild neurological problems.

That finding posed a puzzle, however. Not only are TGF-β1 and TGF-β3 structurally similar, but researchers think that they alter cell behavior by binding to the same receptor. Kuchroo’s team found a possible explanation for this mystery after comparing gene-activity patterns in TH17 cells induced by the two versions of TGF-β. The cytokines prompted contrasting patterns in approximately 90 genes that encode signal-transmitting proteins, suggesting that TH17 cells “hear” a different message from TGF-β1 than from TGF-β3.

Other key gene-expression differences emerged when the researchers used microarrays to track the activity of the entire genome in TH17 cells stimulated with various combinations of cytokines. Comparing these cells to untreated T cells uncovered more than 400 genes with altered activity. When the team homed in on differences between the cytokine combinations, one group of genes stood out. TH17 cells exposed to IL-6 and TGF-β3 tended to turn down levels of immune-controlling cytokines— such as the anti-inflammatory molecule IL-10 and proteins that coordinate its production. In contrast, cells soaked in TGF-β1 and IL-6 tended to turn up the genes for IL-10 and its associates.

The study indicates that TGF-β3 is a key ingredient for cooking up pathogenic TH17 cells, the researchers conclude. In the first step, IL-23 boosts or sustains TGF-β3 production by TH17 cells. Then TGF-β3 might spur TH17 cells to cause damage by dialing back activity of genes for immune-soothing cytokines such as IL-10.

Segal says the work deserves high marks because “it did a nice job in terms of comparing different cytokine cocktails that can induce pathology.” But the researchers found that TH17 cells stimulated with IL-1β, IL-6, and IL-23 were just as damaging as cells induced with TGF-β3 and IL-6, notes immunologist Kingston Mills of Trinity College Dublin in Ireland. “It’s not the only pathway,” he says. IL-1β, in combination with IL-6 and IL-23, might evoke a similar effect, but in a different way.

Researchers have already tried unsuccessfully to tamper with TH17 cells in MS patients. An antibody that blocks IL-23, ustekinumab, performed poorly in clinical trials. The new findings could provide another treatment avenue, Kuchroo and Segal say. TGF-β3 itself offers a promising new target for drug designers, according to Kuchroo. However, because it is essential for functions such as angiogenesis—the growth of new blood vessels—Segal says he’d prefer to aim at proteins downstream of TGF-β3. If researchers do target these molecules, they might discover how to keep TH17 cells on the straight and narrow.

Key open questions

• What is the role of TH17 cells in MS?
• How do pathogenic TH17 cells provoked by IL-1β, IL-6, and IL-23 differ from those induced by TGF-β3 and IL-6?
• What molecules released by TH17 cells cause pathology?

Image credit

Thumbnail image on landing page. "Dark side of the moon" by Kraigsta, 2009. Released into the public domain.