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. 2013 Sep;12(4):1069-78.
doi: 10.1016/j.arr.2013.04.003. Epub 2013 May 6.

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

Jon Hazeldine  1 , Janet M Lord
Affiliations

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

Jon Hazeldine et al. Ageing Res Rev. 2013 Sep.

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.

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Figures

Fig. 1
Fig. 1
Mechanisms of natural killer cell cytotoxicity (NKCC). NK cells directly eliminate transformed cells through one of two contact-dependent mechanisms. (A) The granule exocytosis pathway. Following target cell recognition and activation, NK cells secrete an array of lytic effector molecules into the immunological synapse. These molecules include the pore-forming protein perforin and a family of serine proteases termed granzymes. Binding of these proteins to the target cell surface triggers their uptake into endosomes, which are subsequently lysed by perforin, resulting in the release of apoptosis-inducing granzymes into the cytoplasm (Thiery et al., 2010, Thiery et al., 2011). Shown in the figure are the 3 pathways by which granzyme B mediates target cell death. (1) As an aspase, granzyme B cleaves and directly activates effector caspases (e.g. caspases 3 and 7), which subsequently induce target cell apoptosis by degrading proteins involved in DNA repair (e.g. poly ADP ribose polymerase (PARP)) and activating the endonuclease caspase-activated DNase (CAD) by degrading its inhibitory binding partner, inhibitor of caspase-activated DNase (iCAD). (2) As well as activating caspases 3 and 7 directly, granzyme B can indirectly activate these proteases by cleaving the BH-3 family protein BH3-interacting domain (BID) death agonist into its truncated form (tBID). tBID translocates to the mitochondria, where it induces permeabilisation, leading to the release of cytochrome c. The presence of cytochrome c along with other pro-apoptotic proteins in the target cell cytosol results in the activation of the initiator caspase, caspase 9, which mediates cell death by cleaving and activating caspases 3 and 7. (3) In addition to inducing caspase-dependent target cell death, granzyme B can trigger caspase-independent cell death by directly cleaving proteins involved in DNA repair and maintenance. These proteins include PARP, inhibitor of caspase-activated DNase (iCAD) and the nuclear protein lamin B. (B) Death receptor ligation. Activated NK cells express on their surface Fas ligand (FASL) and TNF-related apoptotic inducing ligand (TRAIL), which bind their cognate receptors, Fas and TRAIL-R respectively on the target cell surface. Ligand binding leads to receptor oligomerisation and the recruitment of the cytosolic adaptor protein Fas-associated protein with death domain (FADD) along with the initiator caspases, pro-caspase 8 and 10 to the target cell membrane. Formation of this complex, referred to as the death-induced signalling complex (DISC), triggers the activation of caspases 8 and 10, which subsequently induce apoptosis by activating caspase 3 either directly via cleavage or indirectly by generating tBID, which leads to cell death by driving mitochondrial permeabilisation, cytochrome c release and caspase 3 activation.
Fig. 2
Fig. 2
Features of the ageing process proposed to result in part from age-associated changes in NK cell biology. It is hypothesised that alongside the previously described association between decreased NKCC and an increased susceptibility to viral infection in older subjects (Levy et al., 1991, Ogata et al., 1997, Ogata et al., 2001) that the age-related reduction in perforin-mediated cytotoxicity and cytokine/chemokine production along with changes in NK cell surface phenotype have additional consequences for the health of older adults. These are proposed to include: (1) the accumulation of senescent cells and the subsequent development of such age-related pathologies as sarcopenia and cardiovascular disease (Sagiv et al., 2012), (2) slower resolution of inflammatory responses and increased immune-mediated tissue damage due to impaired NK-mediated elimination of neutrophils, (3) increased reactivation rates of latent Mycobacterium tuberculosis (TB) due to impaired production of IFN-γ by NK cells and reduced recognition of TB-infected monocytes and macrophages by the activating receptor NKp46 and (4) poorer vaccination responses as a result of impaired NK cell-dendritic cell (DC) cross-talk due to reduced IFN-γ production by activated NK cells.
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