’Genetic switch’ proves two mechanisms exist by which immune system cells differentiate

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 a researcher at the University of Georgia calls a “lucky lab accident,” a new “genetic switch” involved in T-cell maturation has been discovered. The finding, published today in Nature Immunology, could help find ways to “restart” T-cell production in older adults and victims of disease such as AIDS.

“What this means is that when these cells grow or differentiate, it is a two-stage process,” said Dr. Nancy Manley, an assistant professor of genetics at UGA and an adjunct assistant professor at the Medical College of Georgia. “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 on the research paper were Brian Condie and Dong-ming Su of the University of Georgia and Won-jong Oh and Samuel Navarre of the Medical College of Georgia. The work is supported by a grant by 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–is also involved in immune response. Thus, mice with the nude gene have no T-cells and as a result have virtually no means of fighting off disease unless they are raised and live in germ-free environments.

In what Manley calls a “lucky accident,” the team, in trying to produce a mouse with a fluorescent protein under control of the nude gene, came up with something entirely unexpected. The mouse, with the nude gene absent, should have been born completely without hair. Instead, its hair came in and grew normally.

At first, the team though 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 (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,” said 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 from their teenage years to midlife.

Likewise, certain diseases can kill off T-cells, making the body vulnerable to a host of infectious diseases, almost as if their bodies had suddenly grown very old. Armed with new evidence about the action of thymic epithelial cells, researchers may one day be able to selectively turn on T-cell production–making numerous disease far less virulent or even extending life.

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,” said 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.”

With more than 100 of the mutant mice now flourishing in germ-free conditions in Manley’s lab, the work continues