Cytokine May Alter T Cell Populations, Modulate Inflammation

In a healthy immune system, inflammation-suppressing regulatory T cells and inflammation-stimulating T helper 17 cells stay in a healthy balance. Too many regulatory T (Treg) cells may cause a vulnerability to tumors or infection, and too much T helper 17 (Th17), a tendency toward autoimmunity.

Many researchers are trying to find the factors that drive naive T cell differentiation into these specialized populations. Through the convergence of several experiments, Vijay Kuchroo, the Samuel L. Wasserstrom professor of neurology in the field of inflammatory disease at HMS and Brigham and Women’s Hospital, and colleagues found that the cytokine interleukin-6 (IL-6) stimulates Th17 cell generation. It does so in the presence of transforming growth factor-beta (TGF-beta), a factor that on its own produces regulatory T cells, they report in the May 11 Nature.

Differentiation dichotomy. Inactive antigen-presenting cells (APCs) cause naive T cells to differentiate into regulatory T cells in the presence of TGF-beta; they do so by inducing Foxp3, a transcription factor that drives regulatory T cell differentiation. In the case of infection, however, activated APCs produce additional soluble factors including interleukin-6 (IL-6). This cytokine inhibits the induction of Foxp3, while inducing T helper 17 cell differentiation.

“It’s a yin and yang. Nature uses the same components to protect from inflammation and to fight infection,” said Kuchroo. Not only do these Treg and Th17 cells functionally oppose one another, “there is a dichotomy in their generation. It depends on what’s in the milieu at the time.”
The findings stem from the work of first author Estelle Bettelli, HMS instructor in neurology at BWH, who had been trying unsuccessfully to confirm a hypothesis that IL-23 induces Th17 generation.

Concurrent work by colleague Mohamed Oukka, HMS instructor in neurology at BWH, turned Bettelli’s frustration into a fortuitous observation. Oukka was examining mice genetically engineered to allow him to track cells that express Foxp3, a transcription factor known to cause differentiation of naive T cells into Treg cells. Oukka wanted to know how different cytokines affect Treg cells. In the presence of both IL-6 and TGF-beta, he saw no Treg-cell generation. “To our surprise,” said Kuchroo, “the resulting cells produced IL-17,” a marker indicating the creation of Th17 rather than Treg cells. Their observations suggest that IL-6, not IL-23, is a toggle for the generation of these functionally reciprocal T cell types.

A separate line of investigation illustrated the delicacy of the balance between these cells. Howard Weiner, the Robert L. Kroc professor of neurology at HMS and BWH, and co–first author Yijun Carrier, a research fellow in his lab, created mice designed to resist autoimmunity by engineering activated T cells to produce TGF-beta and promote regulatory T cell creation. Yet when immunized with a myelin antigen, the mice did not resist autoimmunity. They died from it.

Weiner’s mutation may protect against autoimmunity in some circumstances, but in this case, it swung wildly in the opposite direction. The vaccine Weiner used contained tuberculosis bacteria that triggered an immune response. The mutant mice overproduced TGF-beta because of the mutation, but they also produced IL-6 because of the infection. Later analysis showed the mutant mice’s brains contained double the proportion of inflammatory Th17 cells and just one fourth of the counterbalancing Treg cells compared to immunized wild-type mice.

—Elizabeth Dougherty

Protocol Identifies Victims of Domestic Violence

More than 10 years ago, a man returned home from Yankee Stadium to find that his wife had cooked a dinner he did not like. So he took a box cutter to her face. It took six hours for Leslie Halpern, then an intern at a Bronx hospital, to stitch up the wounds. Two nights later, the woman was back in the hospital; this time she was dead. The husband was arrested, and Halpern became motivated to find a better way to intervene in intimate partner violence.

About the same time, Thomas Dodson, then an oral and maxillofacial surgeon at Emory University in Atlanta, and his colleagues were finishing up a study that first identified head, neck, and facial injuries as sensitive, but not specific, markers of domestic violence. In an inner-city hospital emergency department, they found, most domestic violence victims had head, neck, and facial injuries, although only one quarter of patients with such injuries were victims of domestic violence.

Now Halpern and Dodson have teamed up in the Oral and Maxillofacial Surgery Department and the Emergency Department at Massachusetts General Hospital to validate and test a quick and predictive diagnostic tool to identify abuse of women, who are at highest risk for these injuries. “Preventive actions cannot be initiated until the diagnosis is made,” they write in the May 2006 Journal of the American Dental Association (JADA).

The gold standard for identifying domestic violence injuries is a self-report, said Halpern, HSDM assistant clinical professor of oral and maxillofacial surgery at MGH. But health care providers may not ask, and patients may not tell.

In the experimental protocol, injuries to head, neck, or face plus a positive answer to any one of three questions (“Have you ever been hit, kicked, or punched in a relationship?” “Have you ever felt unsafe in a relationship?” and “Do you feel unsafe now?”) predict a woman as likely to report injuries due to domestic violence.

In the JADA study, the researchers developed a predictive model based on 200 women who sought emergency evaluation and treatment for nonverifiable falls and assaults. They validated the model in another 100 women. The model protocol correctly diagnosed the presence or absence of domestic violence more than 90 percent of the time.

The researchers are proceeding carefully in rolling out the protocol because of the serious consequences of false positives and false negatives.

“Ultimately, our goal is to make diagnosis in this socially awkward situation as painless, objective, and nonjudgmental as possible without false arrests or returning wives to dangerous settings,” said Dodson, HSDM associate professor of oral and maxillofacial surgery at MGH.

—Carol Cruzan Morton

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