Investigators at St. Jude Children's Research Hospital have discovered a new signaling molecule that prevents immune responses from running amok and damaging the body.
The finding could lead to the development of new treatments for cancer, using vaccines; for autoimmune diseases, such as Type 1 diabetes; and for inflammatory diseases, such as inflammatory bowel disease (IBD) and asthma.
The St. Jude team discovered that specialized immune lymphocytes called regulatory T cells release a protein complex composed of two proteins called Ebi3 and Il12a. This protein complex acts like a brake on the activity of the aggressive immune cells called effector T lymphocytes. A report on this discovery appears in the journal “Nature” Nov. 22, 2007.
The newly recognized protein complex is one of a large group of signaling molecules called cytokines that cells use to communicate with each other. Since the immune system cytokines are called interleukins, the St. Jude team named this protein interleukin-35 (IL-35). Most cytokines stimulate immune system cells by driving the immune attack or causing inflammation. However, IL-35 is one of the few signaling molecules known to inhibit immune system activity.
“The discovery of IL-35 is important because the manipulation of regulatory T cells is a key goal of immunotherapy,” said Dario Vignali, Ph.D., associate member in the St. Jude Department of Immunology, and the paper's senior author. Immunotherapy is the treatment of infections, cancer or other diseases by manipulating the immune system to enhance or restrict its activity. Despite the fact that regulatory T cell-mediated immunotherapy holds promise for patients, the molecules responsible for the cells' ability to suppress immune system activity are largely unknown, a problem that has slowed progress in this field.
The St. Jude team showed that the genes that produce IL-35 (Ebi3 and II12a) are active in regulatory T cells but not in effector T cells and are critical to regulatory T cell function. In fact, regulatory T cells that lack the Ebi3 and II12a genes lose much of their ability to suppress effector T cells. In addition, these regulatory T cells are unable to cure mouse models of an inflammatory disease that closely resembles human IBD.
When the researchers added regulatory T cells to a culture dish with effector T cells, the regulatory T cells dramatically increased their production of the decoded forms (messenger RNA) of the Ebi3 and II12a genes. This suggests that effector T cells had released signals that stimulated the regulatory T cells to decode these genes and make IL-35, the researchers reported.