Telomerase-based approaches to enhance immunity to viruses during ageing

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer's disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant "work" required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).