Maria Ciofani studies the immune system's ability to start and stop its aggression against other cells, in her Jones Building lab. Photo by Jared Lazarus/Duke University Photography
Maria Ciofani is immersed in an identity crisis, though not one of her own making. She studies the Th17 cell, a type of immune cell that is notorious for its adaptability and ever-shifting identities. One moment the cell can be a fighter, protecting the body against bacterial or fungal invaders. The next it can be a peacemaker, quelling the immune response after an infection has cleared.
The mercurial nature of these cells enables the immune system to respond quickly to new threats, but it can also trigger the kind of friendly fire that underlies autoimmune conditions like inflammatory bowel disease and multiple sclerosis.
“The driving force behind my research has been to understand what controls cell identity. If we could identify the mechanisms that switch these T cells from being pro-inflammatory to being anti-inflammatory, then we could have a new way to address autoimmune diseases that arise when Th17 cells behave inappropriately,” said Ciofani, who joined Duke as an assistant professor of immunology in November, 2013.
Ciofani, who conducted her graduate studies at the University of Toronto and her postdoctoral fellowship at NYU, jokes that she chose to go into immunology because of her own indecisive nature.
“It was very interdisciplinary, so for someone who is a little indecisive and likes a little bit of everything, it was perfect because you didn’t have to commit immediately to anything,” Ciofani said. “You have your biochemistry, your molecular biology, and your physiology, all in one spectacular system.”
That system seems well-suited for Ciofani, whose work has already appeared in more than 20 scientific publications, including the esteemed journals Cell, Science, and Journal of Immunology.
Recently her studies on the cells focused called Th17 because they produce interleukin-17, a chemical that helps regulate the immune response. Th17 cells help protect parts of the body that regularly contact substances from the outside world, such as the linings of the intestines and lungs. However, at times they can take this role too far, waging an attack against good bacteria or healthy tissue.
To pinpoint the molecular basis of this mistaken identity, Ciofani’s laboratory uses an iterative systems approach that combines the latest genomic technology, bioinformatics tools, and mouse models of disease
First, Ciofani searches the DNA of Th17 cells for sites bound by master switches that turn on or off hundreds of genes, called transcription factors. Next, she maps out all the transcription factors and the genes they target to create a complex web of inputs, outputs, and interactions that could influence the changeable behavior of these cells.
“That helps us identify possible targets for immunotherapy,” Ciofani said. “By creating these networks, we can get a better idea of what other processes might be disrupted if we target a particular transcription factor.”
One strong candidate has emerged from these analyses so far, a transcription factor called Fosl2. Ciofani “knocked out” this gene in the laboratory, creating tissue culture cells that were missing the transcription factor. She found that the mutant cells essentially underwent an identity crisis, adopting the role of peacemaker when they should have been fighting.
When she knocked out Fosl2 in a mouse model of multiple sclerosis, she showed that the mutant mice failed to develop the symptoms of the autoimmune disease. In both a lab dish and a mouse, toggling this master switch seemed to make Th17 cells assume the identity of peaceable regulatory cells.
“The question is whether we can generate the same result pharmacologically (with drugs),” Ciofani said. “We don’t have that expertise, but I have been talking with MS researchers at Duke and I think it would be an interesting follow-up. After all, that is why we do this work, to have a chance at curing autoimmune disease.”
For a scientist who has been exposed to more than her fair share of identity crises, Ciofani has no doubt she is where she was meant to be.
“I love what I do,” said Ciofani, who admits her main hobby is exercise to prime her mind and body for doing more science. “I feel like the luckiest person. I have always wanted to do science. This is a good choice for me.”
The 37 year-old Toronto native still misses her friends and family in Canada (her parents are both retired; her younger sister is a cardiologist, married with a young daughter). But she is adjusting to life down South. Ciofani says the yes ma’ams and other tokens of Southern hospitality are beginning to feel as familiar as the friendly colloquialisms of her Canadian brethren.