Telomerase induction in T cells: a cure for aging and disease?

Abstract

Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation.