Harvard Researchers Find Genetic Key to T Cell Differentiation

In her rheumatology practice, sometimes Laurie Glimcher has to stand by helplessly as patients display their swollen and hurting joints. She can do little more than prescribe generalized immunosuppressants - medications that alleviate symptoms by suppressing the body's immune response. The danger is that when taken over long periods of time, these medications can make patients susceptible to infection, cancer, and liver damage.

But in her role as a researcher and professor at the Medical School and the School of Public Health, Glimcher has been searching for ways of altering the immune system more selectively than do these medications. That could yield more effective treatments for immune system conditions ranging from rheumatoid arthritis and multiple sclerosis to transplant rejection and infectious disorders. Now Glimcher has hit pay dirt.

In the June 28 Cell, she and her coworkers reported their discovery of a gene that drives T lymphocytes to mature into specialized subtypes, which then play a crucial role in different immune system disorders.

"This is a very significant paper," says William Paul, director of the Office of AIDS Research at the NIH and chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Disease. "It gives us a first explanation as to the key differences between types of T cells that mediate different types of immunological protection. This is important for eventually designing agents that help us manipulate immune responses more specifically than we are able to do now."

While Glimcher's discovery does not translate into new treatments immediately, it gives researchers a molecular handle on the manipulation of specialized groups of T lymphocytes, says Marc Lanser, chief scientific officer of Boston Life Sciences, a biotechnology company that will fund the preclinical development of Glimcher's finding with $1 million. Lanser hopes it will lead to a gene therapy product that could be tested in humans within two years.

When T lymphocytes in a healthy body encounter a foreign substance, they respond to it by maturing from their so-called "naive" state into active T helper cells. Several years ago, researchers realized that the naive cells gave rise to two types of helper cells, T helper 1 and T helper 2. These specialized cells normally mature in just the right balance to orchestrate an attack against the invader. But the system is out of kilter in several immune system disorders. For example, the swollen joints in rheumatoid arthritis contain too many T helper 1 cells, as do organs under assault by the body's defense system in other autoimmune diseases. Conversely, T helper 2 cells greatly outnumber T helper 1 cells in certain infectious diseases and tumors.

Consequently, researchers have set their sights on trying to tip that T helper cell balance as a way to treat immune disorders. Indeed, in mouse models mimicking the autoimmune disease multiple sclerosis, the approach worked and the sick mice recovered. So did mice suffering from Leishmaniasis, a disfiguring parasitic infection.

But even though the basic paradigm has proved promising over and over, researchers lacked good tools to manipulate the T helper cell imbalance. The only way that is possible, to date, involves administering cell signaling molecules such as interleukin-4 or interleukin-12 (or antibodies to them), and these cause so many side effects that they may not be practical therapy in humans, says Glimcher.

The gene that Glimcher's team showed to lead to the maturation of T helper 2 cells, a proto-oncogene called c-maf, may offer a way out of the dilemma. In the immune system, it is expressed only in T helper 2 cells, where it causes the cell to crank up production and secretion of interleukin 4, which, in turn, signals naive T cells to ripen to T helper 2 cells.

The discovery opens the prospect of gene therapy for autoimmune diseases, in which T helper 2 cells are underrepresented. "The immune system is a great system to do that because you could take someone's lymphocytes out, infect them [with c-maf], and give them back," says Glimcher. While much ground still needs to be covered before her first patient overcomes rheumatoid arthritis thanks to gene therapy, Glimcher has made a big step along the way.

The authors of the Cell article, in addition to Glimcher, are I-Cheng Ho and Martin R. Hodge, both in the Department of Cancer Biology, School of Public Health, and John W. Rooney, now in the Department of Molecular and Cell Biology at the University of California, Berkeley.