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IMMUNOLOGY Chemical Switch Shown to Have Early Effect on Immune ResponseOne of the central concerns of immunology is determining the complex paths of communication in the immune system. When a foreign antigen is recognized by a T cell, a conversation takes place between it and other cells of the system. A decision is made to launch a response, either a cell-mediated (type 1) response to contain and kill cells that are cancerous or infected or an antibody (type 2) response to attack a foreign antigen outside the cells. Researchers led by Harvey Cantor have identified a chemical switch involved in the process that may turn up the type 1 response and turn down the type 2. The elements of this chemical communication are cytokines, two of which have an early role in determining the path of the immune response. Interleukin-12 (IL-12), secreted by macrophages, drives the cell-mediated response by telling undifferentiated T cells to become Th1 cells, the helper cells that oversee the type 1 response. Another macrophage cytokine, IL-10, inhibits this response, driving a type 2 response instead. Scientists trying to induce a type 1 response by increasing IL-12 levels have found that doing so indirectly boosts IL-10, effectively counteracting the intended effect. These and other observations have raised the possibility that the immune system might also contain a switch that would turn IL-12 on and IL-10 off. A paper by Cantor and his colleagues in the Feb. 4 Science names a likely candidate for this cytokine switch, Eta-1, or osteopontin, which seems to signal a type 1 response by raising levels of IL-12 and inhibiting IL-10.
Harvey Cantor led the research on a cytokine that has a role in initiating a type 1 immune response. Other contributors to the research include Georg Weber, Vassiiki Panoutsakopoulou, Marie Sanchirico, and Marianne Jansson of Dana-Farber, and Samer Zawaideh of Children's. "There is an increasing realization that the type of immune response is just as important as its intensity or its duration," says Cantor, HMS professor of pathology and chair of cancer immunology at the Dana–Farber Cancer Institute, the senior author on the paper. Imbalances in the levels of type 1 or type 2 immunity may account for many of the effects of certain diseases. An important clue to the nature of this switch was that the decision leading to type 1 or type 2 immunity is imprinted shortly after an antigen encounter. Missing Mouse ResponsePrevious research in vitro had suggested Eta-1 as an early regulator of immunity. With Eta-1 knockout mice generated by collaborators Susan Rittling and David Denhardt of Rutgers University, Cantor and his colleagues were able to study its function in vivo. To test Eta-1's role in type 1 immunity, they observed the formation of granulomas, an inflammatory response caused by microbial infection or, in this case, injection of a foreign substance. The Eta-1 knockout mice were virtually unable to produce granulomas, unless the growths were reconstituted with purified Eta-1. The Eta-1–deficient mice were similarly unable to produce an effective immune response to bacterial infection.
The T cell cytokine Eta-1 has a two-fold interaction with macrophages that leads to a type 1 immune response. (Illustration by Steven Moskowitz, Advanced Medical Graphics) The researchers also tested how the knockouts responded to corneal infection by herpes simplex virus-type 1 (HSV-1), which induces a type 1 response leading to corneal destruction. HSV-1–induced corneal destruction is the leading infectious cause of blindness in developed countries, and studies in animal models have shown that corneal destruction is not induced by the virus itself, but by an autoimmune reaction. "In some cases, host T cells that are specific for the virus are fooled into reacting against their own corneal tissue by the viral mimic," Cantor says. But the Eta-1 knockouts showed no sign of developing such a reaction. When the researchers looked at the lymph nodes of the Eta-1–deficient mice, they found raised levels of IL-10 and virtually no IL-12, suggesting an underlying mechanism for the effect of Eta-1 in this autoimmune disease. A Double-Barreled CytokineTo gain further insight into the function of Eta-1, the researchers looked at the structural properties of the molecule that might allow it to regulate type 1 immunity. The Eta-1 gene has been expressed in several different systems. Osteopontin, as it is generally known, has been studied in bone development, neuronal development, and kidney stone and tumor formation. In every system, Eta-1 seems to act as a regulator. "Depending on where the balance is, it can shift positively or negatively," says Samy Ashkar, HMS instructor in orthopedic surgery at Children's Hospital and first author on the paper.The two roles of Eta-1 in immunity are associated with the way it binds to receptors on macrophages. The researchers found that the production of IL-12 was related to one end of the Eta-1 molecule binding to an integrin receptor on macrophages. Inhibition of IL-10 was linked to a different portion of Eta-1 binding to the CD44 receptor. The two regional interactions enable the molecule to produce two different effects within the same cell. Eta-1 also has the unusual property of being secreted in phosphorylated and nonphosphorylated forms. "Very few secreted molecules are phosphorylated," Cantor says. Melvin Glimcher, the Harriet M. Peabody professor of orthopedic surgery at Children's, with Ashkar found that phosphorylation of particular serines of Eta-1 is required for certain activities, including inducement of IL-12, while phosphates may not be important for IL-10 inhibition. The observation that phosphorylation may regulate Eta-1 function suggests that this chemical modification can alter the activity of a secreted protein as well as intracellular proteins. "The attractive feature of this molecule is that you get a double-barreled effect," Cantor says. "Binding of the same molecule to two different receptors on a cell differentially regulates two early cytokines in a way that sets the stage for type 1 immunity." —Courtney Humphries |
