Genetic alterations in the ageing immune system: impact on infection and cancer

Abstract

The immune system, which is able to distinguish between self and non-self, is programmed to protect the organism from a huge spectrum of potential foreign invaders. Each T and B lymphocyte bears an antigen receptor of a single specificity, which is determined during development by a unique genetic mechanism that generates millions of different variants of the genes encoding the receptor molecules. When a particular antigen, such as a virus, is encountered, only those lymphocytes bearing the relevant receptors become activated and undergo massive clonal expansion. The expanded antigen-specific B cells produce antibodies, which neutralize free virus in the bloodstream, whereas the T cells, particularly the so-called CD8 T cells, actually kill cells that are infected with the virus. Once the infection is cleared, most of the expanded T cells undergo apoptosis, leaving a small number of memory cells to await future possible encounters with the same virus. During ageing, both latent and acute viral infections lead to increased morbidity and mortality, based, in large part, on the diminished ability of T cells to control the infection. To investigate the underlying mechanism of the T cell defects, we have analyzed the process of replicative senescence in human T cells. Our research has shown that following repeated stimulation with antigen in cell culture, the responding T cells eventually reach an irreversible state of cell cycle arrest, at which time they show loss of gene expression of a key T cell-specific signaling molecule required for proliferation, as well as reduced stress protein production, apoptosis resistance, shortened telomeres and inability to upregulate telomerase. Increased proportions of T cells with identical phenotypes are present in elderly individuals, suggesting that chronic/repeated stimulation of some T cells may lead to replicative senescence in vivo. Genetic modulation of this process may yield novel strategies to augment immune function in the elderly.