December 05, 2004
Harmful Reduction In Immune System Cell Diversity With Age

Why does the immune system become less effective as we age? One reason is that the thymus gland ages. We need to be able to rejuvenate our thymus glands. But another reason is that the T cells in the immune system get old and mess up in a variety of ways. Certain CD8 T cells divide too much and crowd out other needed T cells.

PORTLAND, Ore. Scientists at the Vaccine and Gene Therapy Institute at Oregon Health & Science University have made a discovery that helps explain why our immune system worsens with age. The work was led by Janko Nikolich-Zugich, M.D., Ph.D., a senior scientist at the VGTI. The scientists hope this new information can be used to better protect the elderly from infectious diseases by finding ways to slow or stop the degradation of the immune system. The research results are printed in the current edition of the Journal of Experimental Medicine.

"One of the major components of the immune system are T cells, a form of white blood cell. These cells are programmed to look for certain kinds of disease-causing pathogens, then destroy them and the cells infected by them," said Nikolich-Zugich who also serves as a professor of molecular microbiology and immunology in the OHSU School of Medicine, and is a senior scientist at the OHSU Oregon National Primate Research Center. "Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse, potentially resulting in a higher level of susceptibility to disease. We think we have found one of the key reasons behind this age-related susceptibility."

Specifically, in old age, the number of CD8 T cells diminishes. CD8 T cells have two functions: to recognize and destroy abnormal or infected cells, and to suppress the activity of other white blood cells to protect normal tissue. The scientists believe that late in life a different kind of CD8 T cell is increasingly produced by the body. These cells, called T cell clonal expansions (TCE), are less effective in fighting disease. They also have the ability to accumulate quickly as they have a prolonged lifespan and can avoid normal elimination in the organism.

In the end, these TCE cells can grow to become more than 80 percent of the total CD8 population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

To conduct the research, scientists at the VGTI studied mice, which have immune system function very similar to humans. The scientists found the aging mice to have greater TCE levels than normal mice, a less diverse population of CD8 T cells and reduced ability to fight disease. In addition, the scientists were able to show that increasing TCE cells in a normal, healthy mouse reduces that animal's ability to fight disease.

"While this work is still in the early stages, we think it might be of great value," explained Nikolich-Zugich. "If we can find ways to limit the production of TCE in the aging, we might be able to keep their immune systems strong and better able to fight disease. To provide a real-life example: A flu vaccine shortage like the one we are witnessing might be less concerning if elderly Americans were made less susceptible."

During development the immune system's cells reshuffle an area of DNA in many ways to create T cells that have many different antibody active binding sites to bind to different kinds of antigens (antigens being a large assortment of things including pollen, bacteria, viruses, and yet other potential targets). For each potential invading pathogen we need a small number of immune cells that will recognize it and in response divide rapidly to scale up to meet the challenge of binding to and destroying that invader.

When these TCE cells, which make only a very small number of kinds of antibodies, divide too much they basically squeeze out the other types of T cells. When a pathogen comes along that does not match what the TCE cells can handle then the TCE cells basically refuse to die off to make room for the other types of T cells that can handle the pathogen. This prevents a proper immune response from happening.

In a way the TCE cells pose a problem similar to cancer. They divide too much and squeeze out cells that do necessary jobs. In another way the TCE cells are similar to the T cells that cause auto-immune diseases. They propagate too much to create antibodies that are not needed (in the case of TCEs) or even harmful (in the case of T cells causing auto-immune disorders). It would be interesting to know whether some auto-immune disorders are caused by TCE cells and whether people who suffer from auto-immune disorders have less diverse T cell populations.

In a way this report is good news for people suffering frmo auto-immune disorders because it focuses attention on the need to be able to very selectively eliminate large subsets of immune system cells. A therapy developed to eliminate TCE cells might also be adaptable to use against T cells that are causing auto-immune disorders. Effectively the pool of people who need to have their immune systems selectively pruned back has just gotten a lot larger. This increases the odds of more resources being deployed to develop such therapies.

But what sort of approach will yield a useful way to selectively prune back unwanted T cells? Maybe monoclonal antibodies designed to attack each clone population. That requires being able to characterize each clone population and to find a way make antibodies against it. How hard is all that? I have no idea. Anyone know?

Share |      Randall Parker, 2004 December 05 01:34 PM  Aging Studies

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