Soares, Maria Godinho Alves Vieira Duarte; (2002) Regulation of human naive and memory T cell populations by apoptosis and replicative senescence. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The immune system confers protection by maintaining naive and memory T cell pools capable of responding to both new and recurrent infections respectively. However, these pools of lymphocytes are under constraints that may limit their persistence in vivo. Apoptosis and replicative senescence are known to control T cell numbers, and their regulation is of critical importance to the maintenance of lymphocyte pools. In this work it was found that naive CD45RA+ T cells can be induced to proliferate and survive in vitro by IL-7, while maintaining a naive phenotype, suggesting that this could be a mechanism that maintains the naive T cell pool during ageing. However, cytokine-induced proliferation was associated with telomere shortening in vitro. Telomere shortening was also observed in vivo in CD45RA+CD4+ T cells during ageing, suggesting that, although there are mechanisms allowing the maintenance of this pool, the system maintains control of the expansion by limiting the replicative capacity of these cells. Using EBV infection as a model of T cell anti-viral responses in humans, it was found that the expanded populations of antigen-specific CD8+ T lymphocytes in the blood of patients with acute infection are susceptible to apoptosis in vitro and in vivo. Increased apoptosis of the expanded virus-specific pool is thought to prevent their overexpansion and to mediate the down-modulation of the response upon disease resolution. To enable the persistence of a virus-specific population, some cells must escape apoptosis during the acute disease. An important observation was that, although highly expanded, the virus-specific cells maintained telomere length during acute infection that was associated with increased telomerase activity. This suggests that cells that are initially rescued from apoptosis to form the memory pool have preserved replicative potential. However, in chronically infected patients over one year post acute disease, telomere erosion may eventually limit the replicative capacity of these cells. Taken together, these findings suggest that, despite their different characteristics, naive and memory T cell pools can be regulated by apoptosis and replicative senescence.

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