IMMUNOLOGY

Signal Gives Green Light to Immune Forces

Cytokine Shifts T Cell Fate from Inhibiting to Effecting Immune Response

HMS researchers have delineated the role of the immunoprotein interleukin-6, finding that it serves as a sensitive toggle between the body’s status quo and immune defense.

In a recent trilogy of papers, Vijay Kuchroo, the Samuel L. Wasserstrom professor of neurology at HMS and Brigham and Women’s Hospital, and BWH colleagues Thomas Korn, research fellow in neurology, and Estelle Bettelli and Mohamed Oukka, instructors in neurology, have illustrated the reciprocal relationship between two types of immune cell, T regulatory (T_reg) cells and effectors known as Th17 cells. Interleukin-6 (IL-6), a cytokine produced upon infection, determines the fate of these two cell types before their creation and their action later in life. So crucial is IL-6’s immunologic role that a “backup plan” exists in case the cytokine is absent.

The cytokine interleukin-6 plays a crucial role in activating the body’s inflammation response, according to a study by (clockwise from top right) Vijay Kuchroo, Anneli Jaeger, Amit Awasthi, Mohamed Oukka, Estelle Bettelli, and Thomas Korn.

T Cell Fate Decisions
The research team first established that T_reg and Th17 cells are linked by IL-6 in the May 11, 2006, issue of Nature (see Research Briefs, Focus, June 9, 2006), a study that soon sparked further investigations. “It’s explained a number of phenomena in the immune system,” said Kuchroo.

The immune system has always had aspects that have left scientists baffled, partly due to the system’s intricate job of arming weapons against infection and disarming them to prevent autoimmunity, according to the need. “Nature has created such a wonderful mechanism,” said Kuchroo. When it’s healthy, the body keeps itself in a self-tolerant state, repressing inflammation and autoimmune reactions. This maintenance is carried out by regulatory T cells, which suppress the activity of their immune cell siblings and keep them from attacking their own flesh and blood. As Oukka pointed out, “If you don’t have regulatory T cells, you’re pretty much dead.”

T_reg cells are constantly produced from naive T cells through mixing with the ever-present protein transforming growth factor-beta (TGF-beta). The cells’ destinies, however, change when a foreign pathogen attacks. An infection instantly induces the production of IL-6, and when this interleukin combines with TGF-beta, T cells are blocked from becoming T_reg cells and are forced to become Th17 cells instead. These, in turn, produce IL-17, a cytokine that induces inflammation and other autoimmune responses—and suppresses the T_reg cells that would normally quell that response.

Kuchroo wanted to take these findings further: “We asked, if IL-6 is so important, what happens to a mouse that doesn’t have it?” They demonstrated the answer to this question in their study appearing in the July 26, 2007, Nature. Using genetically engineered mice lacking IL-6, the researchers immunized them to induce autoimmune disease and observed the animals’ T cell response. As the researchers had postulated, without IL-6, the mice produced large amounts of T regulatory cells. Then, to see what the deluge of T_reg cells might have been masking, the researchers depleted the T_regs in the IL-6–deficient mice. The mice immediately began producing Th17 cells.

If IL-6 wasn’t producing Th17 cells, what was? “That’s when we discovered IL-21. It seems to take over that role,” said Kuchroo. IL-21, another cytokine produced by T cells, serves as both a booster and a substitute for IL-6, inducing moderate inflammation and suppressing generation of T_reg cells. Moreover, Th17 cells themselves produce large amounts of IL-21, creating a feedback loop that further amplifies the inflammatory IL-17–producing T cell response.

Tissue Specificity
While determining the actions of T_reg and Th17 cells at their inception, Kuchroo and his colleagues also investigated how the cells behave later in life and what they did when specific organs in the body became inflamed in an organ-specific autoimmune disease. In the April 2007 issue of Nature Medicine, Kuchroo and Korn sought out antigen-specific T_reg cells. Previously, there had been some confusion about whether these cells are induced during an autoimmune reaction.

Using T_reg cells tagged with fluorescent proteins in mice with the murine equivalent of multiple sclerosis, Korn showed that antigen-specific T_reg cells do exist. When the inflammation occurred in an organ during an autoimmune reaction, both the T_reg and Th17 cells traveled to the target tissue. Once the T_reg cells got there, however, they were ineffectual. “The T_regs were there, we could see them, but they still didn’t inhibit the onset of inflammation,” said Korn.

Korn and Kuchroo took these apparently deficient T_regs from the CNS and put them on non–CNS-derived cells from the same immunized animal. There, the T_regs functioned normally. “This means that something in the inflamed environment is inhibiting the T_regs and thus propagating autoimmune inflammation,” said Bettelli.

The researchers found that the T_regs’ failure to suppress inflammation in the CNS was due, again, to their nemesis, IL-6, which was produced by the inflamed CNS tissue along with another cytokine, tumor necrosis factor (TNF). Together, these two suppressed T_reg activity and protected the pro-inflammatory T cells from T_reg inhibition, thereby
promoting inflammation.

This trilogy of papers has larger implications, according to Kuchroo. “I think the study is important not just for basic biology, but in terms of human health,” he said. With this information about the autoimmune properties of IL-6 and IL-21 and their feedback and amplification loops, scientists can target the cytokines when treating autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. Kuchroo notes that clinical trials using IL-6–blocking drugs for juvenile rheumatoid arthritis have “worked like a charm.”

Kuchroo also pointed out that this work could not have been done without the help of long-term collaborators Wenda Gao and Terry Strom at Beth Israel Deaconess Medical Center.

—Lauren Cahoon

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