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UCLA RESEARCH PROVES AGED THYMUS HAS POTENTIAL TO REBUILD HIV-RAVAGED IMMUNE SYSTEM
Until now, scientists believed that the human thymus - the organ that produces the immune system's infection-fighting T cells - stopped functioning after puberty. Today, a paper published by UCLA AIDS Institute investigators in Immunity proves for the first time that the thymus remains functional until at least age 56.
The UCLA breakthrough offers new hope that researchers can learn to harness the thymus to restore T cells lost by patients to HIV, which weakens the immune system by destroying its T cells. The finding also may hold promise for cancer patients who have lost T cells during chemotherapy and radiation therapy.
"Our study focused on exploring three unknowns about the adult thymus," explained Beth Jamieson, Ph.D., principal investigator. "Does the thymus function the same at age 50 as it does at age 5? Does it follow the same process to produce T cells? And do these T cells possess the same diversity of surface markers and receptors?
"The answer to all three questions was a resounding 'yes,'" Jamieson said.
Thymus: Boot Camp for T Cells
Finding the answers to these questions involved painstaking detective work to trace the T cell from its origin. The T cell begins life in the bone marrow as a stem cell before traveling to the thymus. There, the immature T cell - called a thymocyte - undergoes an intricate education process in which the thymus teaches it to distinguish between host, foreign and infected cells.
Once the T cell reaches maturity, the thymus dispatches it via the blood to a defense post in the body tissue.
"The thymus operates like a boot camp that trains T cells to attack specific enemies," explained co-investigator Jerome Zack, Ph.D., associate director for basic science at the UCLA AIDS Institute. "Thymocytes must make the pilgrimage through the thymus and fully evolve before they can help the body fight infection."
The Road to Maturity
Several processes take place concurrently as thymocytes mature in the thymus. First, the thymocyte selects one receptor to display on its surface, which dictates the T cell's target. HIV, for example, can only be attacked by CD8 T-cells bearing receptors that recognize HIV proteins.
Next, the thymocyte expresses an array of cell-surface markers. The type and number of surface markers acquired and then discarded by a T cell indicates its present stage of maturity.
During the final stage of maturation, the T cell develops into either a CD4 - the "helper cell" that HIV targets, or a CD8 - the "killer cell" that fight back against the virus.
Discovering the Results
To determine whether T cells from the adult thymus undergo the same maturation processes as fetal thymocytes, Jamieson and Zack extracted thymocytes from pieces of adult thymus tissue and applied fluorescent stains to the cell's surface markers.
The team identified the cells' stages of development by running them through a flow cytometer, a sophisticated device that enabled the UCLA researchers to tally the diversity of T cell receptors and markers and to distinguish between immature and mature cells.
"We discovered CD4 and CD8 T cells went through all the main stages of development," noted Jamieson. "They also possessed a variety of markers and receptors in the same ratio to each other as fetal thymocytes.
"Our findings suggest that thymocytes develop and mature in the adult thymus as they do in the fetal thymus," she added. "Contrary to previous scientific belief, the thymus continues to function late in life."
"This means that when our body contracts a disease, the thymus issues new T cells to combat infection," Zack added. "Our immune system is not relying solely on old T cells that the thymus produced before puberty."
A Clinical Drawback
While aging does not interfere with the quality of the thymus' ability to produce T cells, the UCLA team discovered an important difference between the adult and fetal thymus: the adult organ cannot produce the same quantity of T cells as the fetal thymus.
"When we compared the productivity of the adult thymus to the fetal thymus, the adult thymus produced about 15 times fewer T cells than the fetal thymus during the same time period," said Zack. "Because the thymus shrinks after puberty, it is smaller in size and therefore releases fewer T cells into the blood.
"Given enough time, however, we know that the thymus could generate a new complement of T cells to replace those destroyed by HIV," he added.
Implications for HIV, Cancer Treatment
Jamieson and Zack's next step will be to explore whether they can learn to switch the thymus on and off. This could potentially allow treatment of patients with hyperactive or underactive immune systems.
Unlike cancer, where a tumor eventually overwhelms the body, HIV directly attacks the immune system. According to Jamieson and Zack, their research may someday enable the HIV-ravaged immune system to replenish its lost store of T cells.
The UCLA team's findings hold implications for cancer, as well. When cancer patients undergo radiation or chemotherapy, these treatments kill off the healthy T cells as well as the malignant cells. Zack and Jamieson propose that oncologists one day will be able to signal the thymus to regenerate the patients' immune system and replace its destroyed T cells.
Funding and Collaboration
The American Foundation for AIDS Research, the National Institutes of Health and National Institute on Aging provided funding for the UCLA study. Drs. Janis Giorgi, Daniel Douek, Lance Hultin, Scott Killian, Richard Koup, Daniel Marelli and Deirdre Scripture-Adams collaborated with Jamieson and Zack.
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Note: For a copy of the research paper, b-roll suggestions and/or to interview a member of the UCLA research team, please contact Elaine Schmidt or Alan Eyerly at (310) 794-0777.
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