The narrowing of the CD8 T cell repertoire in old age

Abstract

Immune function declines progressively with age, resulting in increased susceptibility of the elderly to infection and impaired responses to vaccines. A diverse repertoire of T cells is essential for a vigorous immune response, and an important manifestation of immune aging is the progressive loss of repertoire diversity, predominantly among CD8 T cells in both mice and humans. Importantly, perturbations in the peripheral T cell repertoire, including reduction of the CD4:CD8 ratio and cytomegalovirus-driven T cell clonal expansions, make a major contribution to the 'immune risk phenotype' defined for humans, which predicts two-year mortality in very old individuals.

Figure 1. Progressive impact of age on the T cell repertoire

Prior to the onset of age-associated changes in CD8 T cell immunity, there is robust thymic export. The diversity of the naïve repertoire is maintained by new naïve T cells and homeostatic proliferation. The memory repertoire is diverse. It starts out with low complexity, which gradually increases with antigen experience. Memory T cells homeostatically proliferate at slightly different rates, but this is not manifest as TCEs until later. With age, the thymus involutes, and fewer naïve T cells are exported. With increasing antigen experience, many naïve cells convert to the memory pool. Together, this leads to reduced numbers of naïve T cells and dysregulated homeostatic proliferation, driving more naïve cells into the memory pool. The diversity of the naïve T cell pool becomes extremely limited, resulting in a greater dependence on fortuitously cross reactive memory cells to respond to new antigens, and impairing the quality of the response. The memory repertoire becomes increasing dysregulated with the appearance of TCEs, which limits repertoire diversity. Chronic infection with CMV further drives the development of very large clonal expansions and immune senescence.