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IMMUNOLOGY Mouse Model Devised that Develops Asthma Strengthens Evidence for Transcription Factor as Autoimmune Therapeutic Target The immune system exists in a delicate balance, and sometimes its purposeful actions turn against the body when the balance is tipped. When a team led by Laurie Glimcher, the Irene Heinz Given professor of immunology at HSPH and an HMS professor of medicine, discovered a transcription factor two years ago that seemed to control one side of this balance, they knew they had found a molecule that could affect several diseases. The factor in question, which they named T-bet, seemed to determine the actions of helper T cells, orchestrators of the immune response. In companion papers in the Jan. 11 Science, the team shows that mice they engineered to lack T-bet offer evidence for their hypothesis. The mice have a skewed immune response and spontaneously develop symptoms of asthma. The finding not only helps prove the case for T-bet as an important therapeutic target in several diseases but provides a new model for studying asthma. The balance of the T cell response determines the nature--and repercussions--of the immune counterattacks. Precursor helper T cells (top) can differentiate into Th1 or Th2 cells, regulated by tissue-specific factors like T-bet. Th1 cells orchestrate cell-mediated responses, while Th2 cells activate antibody and allergic responses. In mice lacking T-bet (bottom), the balance between type 1 and type 2 immunity is tipped in favor of a type 2 response. The result: mice develop asthma and are less able to combat infection. But such an effect might help protect against disorders like autoimmunity and transplant rejection. Illustration by Jeff Cleary Beginning with a common precursor, helper T cells differentiate into two types that then determine what kind of immune response an organism will launch. Like generals in a battle, helper T cells decide how to respond to an attack: Th1 cells activate macrophages and other inflammatory cells and send in cytotoxic T cells like ground troops to seek and destroy infected cells; Th2 cells round up B cells to deploy an arsenal of antibodies targeted to enemy antigens. The importance of this decision is underscored by the long list of diseases caused when one strategy overwhelms the other. Too much cell-mediated immunity can result in autoimmune diseases and transplant rejection while overly aggressive antibody responses lead to allergies and asthma. T Cell Tuner When Glimcher and Susanne Szabo, a postdoctoral fellow in her lab, discovered T-bet, they found that it is a powerful regulator of type 1, or cell-mediated, immunity in vitro. T-bet expression enhances the production of interferon-gamma, the hallmark type 1 cytokine, and inhibits levels of type 2 cytokines, directing precursor helper T cells to differentiate into Th1 cells. Its expression can even convert fully polarized Th2 cells into Th1 cells, offering the promise that either inhibiting or enhancing T-bet might sway the immunological balance of several diseases. A preliminary study on human lung tissue found lower levels of T-bet expression in several asthma patients compared with nonasthmatics, suggesting a role for T-bet in the human disease. Animal models of human asthma are tricky because of differences in airway responses and because the causes of the human disease are varied and sometimes elusive. Many current models involve sensitizing mice to an antigen such as ovalbumin and then challenging them with it to provoke an allergic reaction. "That's the model we were going to use," said Glimcher. "However, we didn't have to actually use antigen-induced asthma because these mice spontaneously develop asthma." Not only did the mice have inflammation and hyper-reactive airways, they also showed smooth muscle proliferation and fibrosis that marks the chronic disease but is difficult to reproduce in models. Susanne Szabo and Laurie Glimcher hope that targeting T-bet may help bring equilibrium to diseases of immune imbalance. Photo by Steve Gilbert "The T-bet knockouts are more like some forms of human asthma where we can't identify a trigger," said Jeffrey Drazen, HMS professor of medicine at Brigham and Women's Hospital, editor-in-chief of The New England Journal of Medicine, and a co-author of the study. If a lack of T-bet proves to be a feature of the human disease, then the model will have the advantage of using a common downstream pathway, rather than one of the multiple antigens that could elicit symptoms of asthma. The asthmatic phenotype was observed in knockouts with one copy of the defective gene as well as those with both, implying that a simple tip of the balance is enough to cause disease. That is a good sign for drug development because any potential therapy targeting T-bet would not need to have a dramatic effect to have a clinical benefit. The Best Defense In a companion paper in the same issue of Science, Glimcher's team clarifies the role of T-bet in lymphocytes by studying the cells of the knockout mice. Helper T cells had a profound deficiency of interferon-gamma, confirming the in vitro studies. Her team also looked at a model for studying helper T cell differentiation--infection with the intracellular protozoan Leishmania major. "There are strains of mice that are resistant to Leishmania, and there are strains of mice that are susceptible to it, and that is because they mount a Th1 versus a Th2 response," Glimcher explained. "If you mount a Th1 response, you will combat the organism and kill it off. If you mount a Th2 response, you're in trouble." By breeding the T-bet knockout mice with the resistant mice, the team discovered that absence of T-bet was enough to make the resistant strain just as susceptible to Leishmania infection as the naturally susceptible strain, reversing the Th1 advantage. With evidence that T-bet could influence the outcome of an infectious attack as well as asthma, one of many human diseases caused by a Th2 overbalance, the team has its proof of T-bet's prominence in the immune response. But the knockout study also revealed one surprise: the helper T cells and natural killer cells of the mice had a dramatic decrease in interferon-gamma production, but cytotoxic T cells did not. It seems strange that helper and cytotoxic T cells, which spring from a common progenitor, would have different transcriptional mechanisms to control the production of a key cytokine. Glimcher's lab will be working to elucidate the mechanism of control in cytotoxic T cells. Her team is also studying other disease models that lie on either end of the spectrum of immune balance to determine what effects T-bet might have. They will also be working toward identifying polymorphisms in the gene that correlate with human diseases and searching for compounds that inhibit or enhance T-bet activity. --Courtney Humphries