Limiting Diversity of the CD8 T Cell Repertoire and T Cell Clonal Expansions: The Repercussions of Age on Immunity

ABSTRACT

The immune response diminishes with age. As a consequence, the elderly are highly susceptible to infection and exhibit an increased incidence of morbidity and mortality. One of the most profound changes observed in the aged immune system is the significant decline in diversity of the CD8⁺ T cell repertoire, which occurs in both the naïve and memory T cell compartments. Understanding the mechanisms involved in the deterioration of the CD8⁺ T cell repertoire is important for identifying strategies to improve immunity in the elderly. In this review we discuss the hypothesis that the naïve and memory CD8⁺ T cell compartments become dysregulated by three distinct mechanisms. First, the naïve T cell repertoire progressively declines in diversity due to an age-associated decline in thymic output. Second, skewing of the naïve to memory T cell ratio in favor of memory T cells promotes activation of cross-reactive memory T cells that can mediate inappropriate responses. Third, the memory T cell repertoire is compromised by the appearance of T cell clonal expansions, which we propose are the natural outcome of long-term maintenance of the memory CD8⁺ T cell pool that may occur independently of the ageing environment. Ultimately these events lead to a failure to mount effective immunity to both new and previously encountered pathogens.

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