Bad Influence: Aged environment stifles T cell division (Immunology)
Authors: Leslie Mitch 
Published: August 2003

It's immunology's version of the nature versus nurture brouhaha. Do old T cells malfunction because of intrinsic defects or because the body's internal environment changes? A new study gives ammunition to the environment advocates, showing that one kind of old T cell can recover its youthful ability to divide rapidly when transplanted into young mice. However, the results do not settle the dispute.

Although the number of T cells doesn't decrease as we age, their ability to battle pathogens wanes. Researchers aren't sure what causes this decline, but they have shown that helper T cells, which rouse the immune system to attack, divide unusually slowly in the elderly. Such studies, however, had not resolved whether aging also undermines the cytotoxic T cells that slay cells corrupted by cancer or viruses.

To probe that issue, Zhang and colleagues measured the proliferation of cytotoxic cells in hearty young mice 2 to 3 months old and in decrepit rodents 22 to 26 months old. The researchers gauged the rate of division by measuring the cells' absorption of bromodeoxyuridine, a molecule taken up by dividing cells and slotted into new DNA strands in place of the normal building block thymidine. They tested "naive" cells that had never seen combat, as well as memory cells, veterans that provide lifelong immunity to diseases that the animal has already beaten.

The memory cells reproduced twice as fast in the young mice as in the oldsters. Transplant experiments revealed that the animals' physiology influenced the cells' ability to multiply. Old cytotoxic cells that had been infused into young mice regained most of their youthful fecundity, whereas reproduction of young cells that had been inserted into old mice plunged. "Something about the internal environment of old mice slows down the rate at which T cells divide," says Jonathan Sprent of the Scripps Research Institute in La Jolla, California, leader of the research team.

What might that be? Sprent suggests that the combination of Bcl-2, a protein that suppresses division and makes cells live longer, and interferon-1, one of the immune system's signaling molecules, is responsible. The researchers found that production of both shoots up in the aged animals, and when they blocked interferon with antibodies, the division rate of the old cells perked up.

Sprent cautions that the work does not show reduced infection-fighting ability of the old memory cells. Moreover, the decline in cell proliferation observed in aging mice might not occur as humans get older. Measuring cell division in people is tricky, but a quick test of the idea would be to check concentrations of interferon-1 in elderly folks, Sprent says.

The study identifies two molecular changes that might cause old T cells to slow down. Although the results boost the "nurture" argument, they should hearten the other side as well, says Philippa Marrack, an immunologist at the National Jewish Medical and Research Center in Denver, Colorado. Old cells transplanted into young mice did not reproduce as quickly as young cells infused into the same animals, which suggests that some defects are accumulating in old cells, she says. Just like the nature versus nurture debate, this dispute could stay healthy for a long time.

--Mitch Leslie; suggested by Amir Sadighi Akha

X. Zhang, H. Fujii, H. Kishimoto, E. LeRoy, C. Surh, J. Sprent, Aging leads to disturbed homeostasis of memory phenotype CD8
+
cells.
J. Exp. Med.
195
, 283-293 (2002).
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