in Body's Immune Response
July 10, 1996:
Embargoed for release July 11 to coincide with publication in Nature
Harvard Researchers Identify Key Controller in Body's Immune Response:
Researchers at Harvard School of Public Health and Harvard Medical School discover protein that serves as "master switch" controlling differentiation of T helper cells
BOSTON - In recent years, researchers have realized that the body's arsenal to fight foreign invaders is much more extensive than they had thought only 10 years ago, and they are racing to uncover the molecular basis of its highly orchestrated strategies to ward off disease. Now, immunologists led by Michael Grusby, assistant professor at the Harvard School of Public Health and Harvard Medical School, have scored a major point in this search.
By creating and analyzing genetically engineered mice that lack the gene for a signaling molecule dubbed Stat 4, Grusby was able to show that it plays a crucial role in determining how the body will tailor its T helper-cell response to pathogens.
Stat 4, as well as another such protein, Stat 6, are the master switches that control the differentiation of T helper cells, says Grusby. He adds that because differentiated T helper cells play a critical role in dictating the outcome of immune responses, identifying the master switches paves the way for learning how to manipulate them. And that, he says, "holds great promise for the treatment of immune system diseases."
The finding will be published in the July 11 issue of Nature, back-to-back with a similar report from a competing laboratory.
The study helps explain a phenomenon, discovered 9 years ago, that the body boasts two distinct types of T helper cells. When the immune system needs to recruit T helper cells for a fight against a pathogen, it does so by instructing precursor T cells, which have not yet encountered a foreign antigen, to mature into either of two kinds of helper cells. These two, T helper 1 and T helper 2, differ by the kinds of soluble messenger molecules, or cytokines, they produce and therefore by the type of physiological defense mechanisms they rally to carry out the immune response.
Researchers quickly found that each immune response requires a certain balance of T helper 1 to T helper 2 cells, and that this balance was directly linked to the outcome of immune system diseases. One study after another implicated inappropriate ratios of these helper-cell subsets in immune system disorders ranging from transplant rejection to parasitic infections and autoimmune diseases, and some found that tilting the balance effectively treated animal models of, for example, multiple sclerosis.
"Almost every disease that is mediated by the cellular arm of the immune system is in some aspects controlled by T helper- cell subsets," says Grusby. That is why the idea of manipulating the balance of T helper 1 and T helper 2 cells holds such general appeal as a potential new approach to treatment.
In order to learn how to shift T helper-cell ratios, though, researchers first need to unravel the molecular chain of events that ultimately tells a precursor T cell whether to mature into a T helper 1 or T helper 2 cell.
Grusby knew that the initial signal arrives at the outside of the precursor T cell in the form of a cytokine. For example, the docking of interleukin-12 (IL-12) to a cell surface receptor meant the precursor cell was destined to become a T helper 1 cell. But how was that message being relayed to the cell nucleus? What signal ultimately sent the cell on the road to becoming a T helper 1 cell? To test their hunch that a recently discovered family of signaling molecules called Stat proteins might play the role, Grusby and coworkers genetically destroyed in mice the gene for Stat 4 and studied the ability of the mice to generate T helper 1 cells. In the upcoming Nature, the scientists report that the mice indeed failed to respond to the IL-12 in their bodies and consequently made almost no T helper 1 and almost exclusively T helper 2 cells. Their experiments show that Stat 4 is the key element committing the precursor cell to becoming a T helper 1 cell.
This study comes hard on the heels of a report earlier this year in the journal Immunity, in which Grusby showed that Stat 6, another member of the same protein family, commits precursor helper cells to becoming T helper 2 cells.
The authors of the Nature article, in addition to Grusby, are Mark H. Kaplan at Harvard School of Public Health, and Ya-Lin Sun and Timothy Hoey, both at Tularik Inc. in San Francisco.
Editors, please note: This article is directly related to a June 28 Cell article published by Laurie Glimcher of Harvard School of Public Health and Harvard Medical School.