Photo by Theresa Naujack
Clinical Research Division scientists have discovered a mechanism to explain how the immune system gets a boost when it confronts a viral infection.
Researchers in Dr. Thomas Spies' laboratory are finding that virus-infected cells produce surface molecules called MIC, distant relatives of the better-known MHC immune-response molecules.
When MIC binds to a receptor called NKG2D on T-cells - immune-system cells that seek out and destroy infected cells - the T-cells get a stimulatory signal that augments their ability to destroy virus-infected cells, induces their proliferation and causes them to produce immune response molecules called cytokines.
The findings have potential applications for therapy of infectious diseases and cancer and could help explain the genesis of autoimmune diseases.
Dr. Veronika Groh, lead author of the study, said that the stimulatory signal provided by MIC-NKG2D acts at the final stage of T-cell maturation, past the point at which T-cells normally are activated to combat invading microorganisms.
"What we've found is sort of a last-resort mechanism for T-cells to be activated against cells infected with virus," she said. "It enables T-cells to respond to a pathogen when all other systems have been exhausted."
Other investigators for the study, published in the March edition of Nature Immunology, include Rebecca Rhinehart, a technician in Spies' lab, Dr. Julie Randolph-Habecker, a postdoc in Dr. Beverly Torok-Storb's lab, and Dr. Stanley Riddell and his postdoc Dr. Max Topp.
Groh said most T-cells require two stimulatory signals to proliferate and kill infected cells. The first signal is mediated by T-cell receptors, proteins on the surface of T-cells thar recognize bits and pieces of viruses or bacteria displayed on the surfaces of infected cells.
Secondary, or costimulatory, signals are mediated by other types of receptors, including NKG2D, that bind to different types of surface molecules on infected, stressed or what are known as professional antigen-presenting cells.
Spies' lab published papers in 1998 showing that stressed cells in the gastrointestinal mucosa as well as epithelial tumors produce MIC molecules. Several viruses trigger the same stress pathway, known as the heat-shock response, leading the research team to wonder whether viral infection also would induce synthesis of MIC.
The new study examined whether cells infected with cytomegalovirus, a virus that can cause complications for bone-marrow transplant recipients and other immunocompromised patients, display MIC molecules on their surface.
Researchers found that one to three days after infection of cells in culture, MIC was present on cell surfaces at levels tenfold higher than uninfected cells. As levels of MIC rose, the amount of surface proteins that display pieces of the virus declined.
Groh said that this finding, along with additional experiments shown in the paper, support the idea that interaction of MIC with the NKG2D receptor helps T-cells mount a late response against infected cells.
The team also found elevated MIC levels in lung sections from CMV-infected patients, demonstrating the physiological relevance of their findings.
Groh suspects that many other pathogenic microorgansims will trigger expression of MIC in the cells they infect.
"We have some preliminary data that suggests that herpes simplex virus also induces MIC," she said, "and we are collaborating with a group that has shown that a type of bacteria called mycobacterium does the same."
Because MIC is expressed by several types of epithelial tumors, their findings may have potential clinical value for treating cancers with T-cell therapy. T-cell therapy, a treatment extensively studied by Riddell and Hutch colleague Dr. Phil Greenberg, attempts to treat cancer and other diseases using T-cells specific for tumors or virus-infected cells.
"T-cells used in this kind of therapy must first be expanded outside the body to generate a large quantity of cells with tumor-fighting properties," Groh said.
"It's probable that such cells could be activated by stimulating NKG2D."
Better understanding of how MIC and NKG2D are regulated may also provide insight into autoimmune diseases, a collection of disorders including lupus and rheumatoid arthritis in the which the immune system reacts against normal body tissues.
Because both MIC and NKG2D have such potent functions, their expression needs to be tightly controlled to ensure that T-cells don't inappropriately react against healthy cells.
"We all have a small number of T-cells that have the potential to react against self proteins, but normally they don't do any harm," Groh said.
"It's possible that MIC expression induced by infection could result inappropriate stimulation of those self-reactive T-cells."