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OHSU Researchers Study Immune System Mystery

   Portland, Ore.

Research helps explain how protective T cells improve their ability to identify and destroy virus-infected cells.

They are the cells that come to the rescue when a virus attacks the human body. T cells are a form of white blood cell that can bind to an infected cell, then destroy it before a virus can replicate itself. Until now, little was known about the specifics of how this unique class of cells works. Now, thanks to the work of researchers at Oregon Health & Science University, scientists have a greater understanding of the important role that T cells play and how this knowledge might be used to develop better vaccines to battle viruses and other harmful pathogens. The research is published in the August issue of the journal Nature Immunology. Mark Slifka, Ph.D., assistant professor of Microbiology and Immunology in OHSU's School of Medicine and an assistant scientist at OHSU's new Vaccine and Gene Therapy Institute is senior author of the paper. J. Lindsay Whitton, M.D., Ph.D., at The Scripps Research Institute in La Jolla, California collaborated with Slifka on the project.

"Certain T-cells, called CD8+ T-cells, are trained to become serial killers. Their role in the immune system is to jump from one cell to another and destroy the infected ones before they become converted into virus-producing factories while leaving uninfected, healthy cells intact," explained Slifka. "In our research we were trying to solve the long-standing mystery of how certain specialized virus-specific T cells learn to identify infected cells much more effectively than other T cells."

Previous research has shown that CD8+ T cells are able to seek out infected cells thanks to viral proteins which show up on the surface of a cell once its been infected. The CD8+ T cells are recruited to sites of virus infection and scan the surface of each cell in the area - a process not unlike a trained police dog "sniffing" for illegal contraband. When a CD8+ locates an infected cell that it recognizes, it then binds with the infected cell, and destroys it, while at the same time flooding the immediate area in a bath of antiviral factors. This release of immunological pesticide not only slows or completely blocks virus replication in nearby infected cells, but also helps prevent the spread of infection to other healthy tissues. After completing its round of immunosurveillance, the CD8+ cell then continues on its mission to find other infected targets.

Researchers found that in a relatively short period of time after the virus first infects the body, CD8+ cells increase their ability to identify the infected cells by over 50-fold. In other words, in a matter of days, the CD8+ cells became significantly better at identifying foreign bodies.

"Before we conducted this research, there were a number of theories as to why some cells were better at their jobs than others. The most widely accepted theory was that the most effective CD8+ cells were simply those with the most binding power. However, our research now shows that the binding power of these cells doesn't change much during the early immune response against a virus. Instead, we were surprised to find that the T cells actually became ultra-sensitive to identifying small amounts of virus inside of infected cells by improving and hard-wiring their internal circuitry. In a sense, the CD8+ cells upgrade their immunological processors in such a way as to more clearly "see" inside infected cells and make the life-or-death decision of whether to destroy that specific cell, or to leave it alone and move on to the next potential target. We believe that this is one of the principal mechanisms underlying the great success of many current vaccines and stands as a concrete reason for parents to always have their children immunized," said Slifka.

Researchers hope this finding can help assist in the fight against a number of diseases by improving vaccine technology as well as aid in the fight against other human ailments, including cancer. One example would be to use this information and future research to develop vaccines teaching CD8+ cells to more efficiently attack and destroy tumor cells before the disease progresses to a terminal state.

This research was funded by the National Institute of Allergy and Infectious Disease, a component of the National Institutes of Health.

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