Grow old or die young: Lymphocyte dynamics in humans

Abstract

In this thesis, we explore the dynamics, T-cell receptor (TCR) diversity and functional characteristics of lymphocytes in various tissue sites in homeostasis and during imbalanced states. While natural killer cells stand out as an interesting cell type for cell therapy against cancer, researchers have questioned whether they may be too short-lived to be effective in the long term. We quantified the lifespan of natural killer cells in vivo and found it to be 94 days — longer than previously reported in the literature. Shifting our focus to T cells, particularly to memory T cells residing in tissues of wildling mice and humans, we examined the differences in their lifespan across various tissue sites compared to their counterparts in blood. Our findings challenge the current notion that tissue-resident memory T cells are long-lived. We found that tissue-resident cells in the skin, the lung and the liver are shorter-lived than those in circulation. Our studies also shed new light on the ongoing debates regarding the lifespan of regulatory T cells and suggest that during adulthood their maintenance is mostly independent of thymic output. Additionally, we investigated the impact of aging and neonatal thymectomy on the functional characteristics and TCR repertoire diversity of naive and memory T-cell populations during adulthood. Contrary to common belief, we found that the immune system of individuals who had been thymectomized at very early age did not show any signs of premature aging. Instead, their TCR repertoire was as diverse as that of age-matched individuals. These insights into the functionality, dynamics, and diversity of lymphocytes throughout the body do not only improve our understanding of the immune system in health and disease, but also pave the way for the development of novel therapeutic approaches.