Griffiths, S.J.; (2011) Chronic cytomegalovirus infection drives the accumulation of memory T cells with low functional avidity during ageing. Doctoral thesis , UCL (University College London).

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Abstract

Immune senescence is associated with a predisposition to infections, poor vaccination responses and early mortality in older individuals. Furthermore, evidence that chronic cytomegalovirus (CMV) infection is a key driver of immune senescence is becoming increasingly recognised. This thesis aimed to investigate the hypothesis that large CD8+ T cell expansions (TCEs) caused by chronic CMV infection during ageing may be instrumental in this association. Data presented here shows CMV-specific CD8+ TCEs that accumulate during ageing are predominately of the CD45RA+ memory phenotype. However, these cells exhibit low Ki-67 positivity and low Bcl-2 levels directly ex-vivo, in addition to poor proliferation and low telomerase activity in response to activation. This indicates they are not accumulating through increased proliferation or resistance to cell-death, and may represent a population close to senescence. These CMV-specific CD8+CD45RA+ memory T cells were also found to display a lower functional avidity for peptide, with higher activation threshold compared with CMV-specific CD8+CD45RO+ T cells. Furthermore, IL-15 was shown to cause CMV-specific CD8+CD45RO+ memory T cells to proliferate and re-express CD45RA in-vitro; adding to existing evidence indicating a role for IL-15 in the homeostatic, rather than antigenic, driven generation of CD8+CD45RA+ memory T cells from a CD45RO+ memory T cell pool. The possible impact of these CMV-specific TCEs during ageing is highlighted by the finding that old CMV positive individuals had significantly shorter T cell telomere lengths than old CMV negative individuals. Therefore, the accumulation of TCEs is likely to impact the CD8 compartment of healthy individuals in two ways; by restricting immune space and also lowering the overall telomere length of the compartment through the accumulation of highly differentiated CD8+ TCEs. Both of these have been shown to increase susceptibility to infection. This study therefore provides further evidence for the detrimental effects of CMV infection and its role in driving immune senescence.

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