The impact of ageing on natural killer cell function and potential consequences for health in older adults

Abstract

Forming the first line of defence against virally infected and malignant cells, natural killer (NK) cells are critical effector cells of the innate immune system. With age, significant impairments have been reported in the two main mechanisms by which NK cells confer host protection: direct cytotoxicity and the secretion of immunoregulatory cytokines and chemokines. In elderly subjects, decreased NK cell activity has been shown to be associated with an increased incidence and severity of viral infection, highlighting the clinical implications that age-associated changes in NK cell biology have on the health of older adults. However, is an increased susceptibility to viral infection the only consequence of these age-related changes in NK cell function? Recently, evidence has emerged that has shown that in addition to eliminating transformed cells, NK cells are involved in many other biological processes such as immune regulation, anti-microbial immune responses and the recognition and elimination of senescent cells, novel functions that involve NK-mediated cytotoxicity and/or cytokine production. Thus, the decrease in NK cell function that accompanies physiological ageing is likely to have wider implications for the health of older adults than originally thought. Here, we give a detailed description of the changes in NK cell biology that accompany human ageing and propose that certain features of the ageing process such as: (i) the increased reactivation rates of latent Mycobacterium tuberculosis, (ii) the slower resolution of inflammatory responses and (iii) the increased incidence of bacterial and fungal infection are attributable in part to an age-associated decline in NK cell function.

Keywords: ADCC; Ageing; Apaf-1; BH3-interacting domain; BID; CAD; CMV; DC; DLN; FADD; Fas ligand; Fas-associated protein with death domain; FasL; IFN-γ; IL-8; Immunesenescence; KIR; MHC; MHC class I-chain-related protein; MIC; MIP-1α; Mycobacterium tuberculosis; NCR; NK cell; NKCC; Natural killer (NK) cells; PARP; PBLs; PMA; T helper 1 cell; TB; TNF-α; TRAIL; Th-1; antibody dependent cell cytotoxicity; apoptosis-activating factor 1; caspase-activated DNase; cytomegalovirus; dendritic cell; draining lymph node; iCAD; inhibitor of caspase-activated DNase; interferon gamma; interleukin 8; killer cell immunoglobulin like receptor; macrophage inflammatory protein-1-alpha; major histocompatibility complex; natural cytotoxicity receptor; natural killer cell; natural killer cell cytotoxicity; peripheral blood lymphocytes; phorbol 12-myristate 13-acetate; poly ADPribose polymerase; tBID; truncated BH3-interacting domain; tumor necrosis factor related apoptotic-inducing ligand; tumour necrosis factor alpha.