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Circuitry of cells involved in immunity, autoimmune diseases exposed

Thursday, 07 March 2013

A healthy human T-cell

New work from the Broad Institute's Klarman Cell Observatory, Brigham and Women's Hospital, Harvard University, MIT, and Yale University expands the understanding of how one type of immune cell -- known as a T helper 17 or Th17 cell -- develops, and how its growth influences the development of immune responses. By figuring out how these cells are "wired," the researchers make a surprising connection between autoimmunity and salt consumption, highlighting the interplay of genetics and environmental factors in disease susceptibility. The results of their work appear in three companion papers in Nature this week.

The researchers concentrated on T cells because of their important roles in clearing foreign pathogens and in various autoimmune diseases. "The question we wanted to pursue was: how does the highly pathogenic, pro-inflammatory T cell develop?" said Vijay Kuchroo, co-director of the Center for Infection and Immunity at Brigham and Women's Hospital's Biomedical Research Institute and a Broad associate member. Kuchroo is also a professor of neurology at Harvard Medical School. "Once we have a more nuanced understanding of the development of the pathogenic Th17 cells, we may be able to pursue ways to regulate them or their function."

The human immune system is in a state of delicate balance: too little activity leaves a person vulnerable to foreign invaders, but too much activity threatens to harm the body it ought to protect. When this delicate balance is broken, it can lead to autoimmune diseases. But little is known about the molecular circuitry that maintains -- or upsets -- such a fine equilibrium.

"We wanted to understand how the body gets the right kinds of immune cells in the right amount, and how it keeps those cells at the right activity level so that they are not too active but also not underactive," said Aviv Regev, a Broad Institute core member and an associate professor of biology at MIT. Regev is also an Early Career Scientist at Howard Hughes Medical Institute and the director of the Klarman Cell Observatory at the Broad. "The value in doing an unbiased analysis is that we're able to understand a lot more about the molecular biology at play and identify novel players in this process."

Th17 cells can promote inflammation that is important for protection against pathogens, but they have also been implicated in diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, and ankylosing spondylitis. Treatment options for some of these diseases, such as psoriasis, include manipulating T cell function.

David Hafler's group at Yale University studies human autoimmune diseases in general and the role of Th17 cells in particular, and has collaborated with Kuchroo's group for many years. "These are not diseases of bad genes alone or diseases caused by the environment, but diseases of a bad interaction between genes and the environment," said Hafler, Gilbert H. Glaser Professor of Neurology, professor of immunobiology, chair of Department of Neurology, and senior author of one of this week's Nature papers.