A substantial deterioration of the naïve CD8(+) T cell pool occurs regularly in humans beyond the age of 65 years. While recall responses to pathogens encountered during youth or adulthood are largely uncompromised, the de novo generation of memory responses by aged naïve CD8(+) T cells is perturbed. In recent years evidence has accumulated that the diminished responsiveness of naïve CD8(+) T cells in aged humans and other mammals coincides with a progressive loss of naïve T cell receptor (TCR) repertoire diversity. In this review we focus on thymic involution and chronic latent viral infections as key factors driving the reduction in naïve TCR repertoire diversity. We present novel insights gained by studying the antigen-driven differentiation of single CD8(+) T cells in young hosts and discuss possible implications of these insights for therapeutic support of the thinned-out clonal T cell repertoire of the elderly by vaccination or adoptive cell therapy.
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