June 14, 1999 A new method of permanently marking T cells has allowed Emory University immunologists and colleagues to overcome one of the most challenging barriers to understanding just how the immune system works. The discovery, which could have far-reaching implications for vaccine development, transplantation and treatment of auto-immune diseases, is reported in the June 10 issue of Nature.
For the first time, scientists are now able to visually distinguish which T lymphocytes become memory cells -- those with the ability to vigorously attack previously encountered pathogens for years after an organism is exposed, either through infection or immunization.
Joshy Jacob, Ph.D., assistant professor of microbiology and immunology at Emory University School of Medicine and nobel laureate David Baltimore, Ph.D., president of the California Institute of Technology, developed the method of irreversibly tagging T lymphocytes with a cell surface protein in genetically engineered mice. The protein, which Jacob calls a "reporter gene," is found in the human placenta but not in mice. "In these mice we can, for the first time, visualize memory T cells, follow their fate in vivo and study their normal physiology in health, autoimmune disease and organ transplantation," says Jacob.
Although the existence of immune memory has been recognized and documented for more than 2,000 years, Dr. Jacob says, research has lagged behind because scientists could not unequivocally identify memory lymphocytes. Until now, there have been no known cell surface markers to distinguish between memory and non-memory (naïve) lymphocytes. The ability to remember and respond to invading organisms -- even years later -- is one of the fundamental features of the immune system. Acute viral infections induce two types of long-term memory -- humoral memory in which B cells produce antibodies to prevent infection by viruses, and cellular immunity, in which T cells activated by specific viral antigens kill the virus-infected cells .
"The key to designing good vaccines is understanding how immune memory works," Dr. Jacob points out. "And the key to understanding how memory works is to have the ability to map and follow these memory cells in animals. The basic science that will come out of this will give us important clues as to what is important for the generation and maintenance of memory."
Following the acute phase of a viral infection, which lasts only a few weeks, the majority of activated CD8 T cells die, while approximately 5 to 10% become memory cells. When memory cells come into contact with the original virus, they are capable of mounting a strong and rapid immune response. Childhood exposure to chicken pox, for example, protects an individual for a lifetime.
Drs. Jacob and Baltimore were able to tag the lymphocytes by creating genetically engineered mice. In these mice, the expression of the reporter gene is blocked by an intervening piece of DNA that separates it from the promoter. The scientists engineered into these same mice a second gene (CRE recombinase) that transiently turns on in the cells activated by virus infection. This recombinase recognizes the intervening DNA sequence and clips it out, thus connecting the promoter directly to the reporter and turning it on permanently by bringing about a DNA rearrangement in the genome.
In order to verify that the tagged cells were in fact memory cells, Drs. Jacob and Baltimore first isolated the cells, then placed them in mice that had never been exposed to the common mouse virus LCMV (lymphocytic choriomeningitis virus). When they exposed the mice to the virus, the mice were protected against infection. When they injected non-memory cells into the mice and exposed them to LCMV, however, they were not protected from the virus. Helen Hay Whitney Foundation and Leukemia Society of America funded this research.
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