The latest research on T cells and aging

Infectious diseases are a significant cause of death among older adults. Many believe that the decline in immune function that occurs with age is largely responsible. Researchers have found that innate immunity—the immune reaction we mount to any invading germ or foreign substance (as distinct from acquired immunity, directed at specific invaders)—remains relatively intact as we age. Although results vary, many studies confirm that natural killer T cell activity is preserved even among the oldest old. Indeed, some studies have suggested that a decline in natural killer cell activity predicts an increasing risk of serious illness. However, there are some age-related declines in T cell function that affect B cell function, specifically the ability of B cells to help T cells fight infection.

Much research is being done in various laboratories to determine just what changes take place in the various sub-populations of T cells as we age. Researchers at the University of Michigan, led by Richard A. Miller, Ph.D., have utilized mouse T cells as models of what happens in the aging immune system. They have looked at the biochemical changes in T cells that are triggered by an encounter with a foreign molecule, changes that prepare the T cell to help fight off the invader. In an article published in 1999, these scientists demonstrated that one of the proteins in the T cell, called protein kinase C-theta, reacts to the presence of foreign antigens by moving to the area of the T cell that is touching the nearby antigen-presenting cell. The number of T cells that could move the protein kinase to the correct area declined in older mice to about half the number that could respond appropriately in young mice, thus reducing the effectiveness of the aged T cells to react properly to foreign substances.

In work published in 2000 in the Journal of Immunology, University of Michigan researchers looked at other proteins and molecules contained within T cells crucial to proper immune responses. Two of these proteins are called LAT and Vav. They demonstrated that the ability of T cells to mobilize these proteins to the surface, where they can properly interact with the antigen-presenting cells, also declines about two-fold in aged mice. At the same time, the mice T cells also experience a two-fold decline in their ability to relocate certain proteins to the nucleus, where these proteins normally set off events leading to T cell division and the formation of clones of protective T cells.

Researchers at the National Institute on Aging have found that cholesterol levels in immune cells increase as we age, even when the amount of circulating cholesterol does not. They studied the ways in which such cholesterol increases affect the activation of T cells and the stimulation of chemokines. Produced in response to acute or chronic inflammation, these cytokines mobilize white blood cells to fight infection or other foreign invaders. Their findings, published in the September 2004 issue of Mechanisms of Aging and Development, suggest that excess non-circulating cholesterol has the ability to disrupt some cell functions and that the aging immune system's inability to regulate cholesterol cells could be a factor in deterioration, or senescence, of the cells themselves.

A discovery made by scientists at the Vaccine and Gene Therapy Institute at Oregon Health & Science University may clarify what causes the immune system to deteriorate as we age. As reported in the December 2004 issue of the Journal of Experimental Medicine, the researchers concluded that age-related depletion of CD8 T cells and an increase in the number of T cell clonal expansions (TCE cells) is a key to increased susceptibility to infection and disease. With the capacity to replace more than 80% of the CD8 T cells whose function is to recognize and destroy abnormal or infected cells, the long-lived TCE cells impair the diversity and efficiency of the immune system. Work with aging mice suggests that limiting TCE production might strengthen elderly immune systems and enhance the body's ability to combat infection and disease.

In a pair of papers published in Mechanisms of Aging and Development in January 2004, researchers James Mittler and William Lee of the University of Albany tested the responses of young T cells transplanted into young and old mice. They found that the primary response, or first response to an invader, was similar whether the T cells were in young or old hosts. However, when challenged again with the antigen the T cells were keyed to, the memory T cells in the younger mice had a much more robust response than the memory T cells in the older mice. These findings indicate that any deficiencies in initial, or innate, immune response in the elderly are likely due to deficiencies in the T cells themselves, whereas cellular conditions in older organisms affect memory cell response, or adaptive immunity.

It is hoped that this increasingly precise understanding of the aging immune system can one day be tested and confirmed in humans, holding out the hope, ultimately, of developing interventions that can boost or at least maintain our immune response over time.