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Columns::December 1, 2003
University hosts first ‘urban congress’ for medium metro cities
Macon, former U. of Northern Colorado administrator, is named registrar at UGA
‘Chick’ chat time
Writing assessment a requirement of freshman applicants for 2006
Adams elected chairman of NASULGC council
Florence Winship, longtime health center physician, dies
Three win staff awards in forest resources
Prof studies how plants can help tolerate environmental damage
Peace Corps opens its only office in Georgia on UGA campus
Kudos
Professional standards: Social work faculty discuss prospects for improving child welfare system
The third degree
Campus News
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| Nancy Manley’s research team discovered the “genetic switch” when trying to produce a mouse with a fluorescent protein under control of the so-called “nude” gene, which causes mice to grow without any hair when it is mutated. (Photo by Rick O’Quinn) |
The naked truth
‘Genetic switch’ controls differentiation in immune system cells
By Phil Williams
phil@franklin.uga.edu
The thymus, a once overlooked glandular structure just behind the top of the sternum, has gained increasing attention from scientists in the past two decades because it is where disease-fighting T-cells mature.
Especially in AIDS patients, T-cell count is a relative indicator of the body’s ability to fight disease. Until recently, however, researchers have understood little about how T-cells are generated.
Now, thanks to what geneticist Nancy Manley calls a “lucky lab accident,” a new “genetic switch” involved in T-cell
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| Nancy Manley discusses an image of a mutant mouse gene with researcher Dong-ming Su. (Photo by Rick O’Quinn) |
maturation has been discovered. The finding, published in October in Nature Immunology, could help find ways to “restart” T-cell production in older adults and victims of diseases such as AIDS.
“What this means is that when these cells grow or differentiate, it is a twostage process,” says Manley, an assistant professor of genetics. “This puts us a step closer to producing important epithelial cells from the thymus in the lab, though we are a long way yet from being able to turn the production of T-cells back on in the human body.”
Co-authors of the research paper were Brian Condie and Dong-ming Su of UGA and Won-jong Oh and Samuel Navarre of the Medical College of Georgia. The work is supported by a grant from the National Institutes of Health.
The primary vehicle for studying T-cell development in the laboratory is the mouse. Researchers have known for years that a gene called “nude”--which causes mice to grow without hair of any kind when it is mutated--is also involved in immune response. Mice with the nude gene have no T-cells and as a result have virtually no means of fighting off disease unless they live in germ-free environments.
Manley’s team was trying to produce a mouse with a fluorescent protein under control of the nude gene, and came up with something entirely unexpected. The mouse, with the nude gene mutated, should have been born completely without hair. Instead, its hair came in and grew normally.
At first, the team thought that a mistake had been made--that the gene had simply not been deleted in this mouse. But when they looked at the thymus in these mice, they found, to their surprise, that it was abnormal but still made some T-cells.
Manley instantly knew that the lab mistake was a golden opportunity. It showed for the first time that the role of the nude gene in T-cell production is far more complicated than previously thought.
The specific cells in the thymus required for T-cell maturation are thymic epithelial cells, or TECs. In the mutant nude mouse, these TECs fail to grow and mature, so no T-cells are made. But in the mutant made in Manley’s lab, the thymus did produce T-cells, although in greatly reduced numbers.
It turned out that the initiation and progression of TEC growth are genetically separable functions in the new mutant mouse. In addition, the team provided the first genetic evidence that an already-known process--called “crosstalk”--is needed for the growth of the thymic epithelial cells.
“Normal nude mice never even start to develop T-cells, because the TE cells remain immature,” says Manley. “These mutants are now telling us how TE cell differentiation occurs. This is the first nude mutant that can produce partially functional TE cells and as a result can also make some T-cells. Now we have to figure out how it happens.”
The practical applications of the research are considerable. The action of the thymus in producing mature disease-fighting T-cells peaks in a person’s mid-teens and then slowly erodes. This is one reason why older people and babies are frequently sickened by or die from diseases that cause little harm to those in midlife.
These results also have further significance in light of recent reports identifying a putative TEC progenitor or “stem” cell. While identification of stem cell populations for specific tissues is a critical step, it is also important to know how to control their growth and development, to allow the production of specific mature cell types in the lab.
“A real problem so far has been that we just can’t make T-cells in the lab,” says Manley. “But now at least we have better tools for understanding how they are made in the body, even though the entire process remains unclear. We can say that now we are closer than ever to being able to make thymic epithelial cells in the lab.” |
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