Mechanisms underlying reduced natural killer cell cytotoxicity with age

Conway, Jessica (2020). Mechanisms underlying reduced natural killer cell cytotoxicity with age. University of Birmingham. M.Sc.

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Abstract

Ageing is accompanied by a marked reduction in natural killer (NK) cell cytotoxicity (NKCC) at the single cell level that is thought to contribute to the accumulation of senescent cells in aged tissues. Although it is established that decreased killing results from reduced perforin secretion in response to co-culture with cancer cells, the mechanisms involved in reduced NKCC towards senescent cells remain unknown.

To investigate reduced NKCC towards senescent cells, we examined the composition of the circulating NK cell pool in healthy young (≤35 years) and older (≥65 years) adults, focussing primarily on highly differentiated CD57+ NK cells as they show reduced function in killing assays. Additionally, we assessed perforin release and mitogen- activated protein kinase (MAPK) activation in NK cells following NKG2D and NKp30 receptor ligation given their role in granule polarisation and NKCC towards senescent cells.

Assessment of the composition of the circulating lymphocyte pool revealed a greater proportion of NK cells in older adults, with a marked increase in the percentage of CD56DIM NK cells and terminally differentiated CD56DIMCD57+ NK cells. Since CD57 expression is associated with immune cell dysfunction, an increased proportion of CD57+ NK cells may contribute to impaired perforin release and NKCC. Whilst we were unable to show that NK cells from older adults secreted lower levels of perforin, though sample size was low, we found no age-associated difference in P38 MAPK activation in NK cells following receptor ligation. Thus, we propose that reduced NKCC with age towards senescent cells may be due to defects in the activation of other MAPK signalling pathways such as ERK.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):