Natural Killer Cells

Natural killer (NK) cells comprise a heterogeneous population possessing immune surveillance functions to combat viral infections and malignancy based on direct cytotoxicity (granzyme/perforin and death receptor mediated) and/or secretion of cytokines and chemokines. In humans the NK phenotype CD3“CD56+ is further characterized into CD56dim (90 %) and CD56bright (10 %) subsets differing in receptor expression and function [98]. Le Garff-Tavernier et al. [99] showed that the frequency of CD3-CD56+ was significantly increased in very old subjects (87.1 ± 4.9 years) whereas the subset CD56bright progressively decreased with age. The concomitant increase of CD56d im NK suggested that the increase in NK frequency observed in older was related to CD56dim maturation. This scenario could impact the ageing immune system as upon activation CD56dim NK cells proliferate less, produce lower amounts of cytokines and are more cytotoxic whereas CD56bright presents higher proliferation levels, produce cytokines (IFN-y, TNF-p, IL-10) and chemokines (MIP-1a, RANTES) but is less cytotoxic [100].

NK cell cytotoxicity relies on the expression of molecules as CD16 (antibody- mediated toxicity), killer immunoglobulin-like receptors (KIR), LIR-1/ILT-2, CD94/ NKG2A heterodimeric receptor which are inhibitory and recognize MHC I molecules as cognate ligands, and the collagen ligand LAIR-1 [101]. NK cells can promote cytolysis of cells lacking MHC I expression (i.e. cancer cells) but they will require an activating receptor such as NKG2C, NKG2D, NKp30, NKp44, NKp46, and NKp80 [102-105]. Interestingly Le Garff-Tavernier et al. [99] showed that the expression of LIR-1/ILT-2 was higher in older subjects compared to adults whereas the production of IFN-y was impaired. Under IL-2 activation NK lysis was more evident in subjects older than 80 years but in absence of stimulus there was a decrease in this function.

Hazeldine et al. [106] also identified an increase in NK cell frequency with ageing in addition to a higher percentage of CD57+ NK cells suggesting a shift towards a more mature circulating NK cell population. They also observed a significant decrease in NK cell cytotoxicity in older adults. The authors showed a decrease of NK cells expressing NKp30 or NKp46 and CD94 (binding partner of NKG2A). More importantly, they found that NK cells from older adults released less perforin into the immunological synapse, which was attributed to a defect in the polarisation of lytic granules to the NK target interface. The group stressed the importance of NK functions decline during ageing as this impairment in NK cells is related not only to lower function in detecting malignancy but has recently been associated with the reactivation of latent Mycobacterium tuberculosis, slower resolution of inflammatory responses, and increased incidence of bacterial and fungal infection [107].

Halama et al. [108] observed in patients with colorectal cancer (CRC; 40-78 years old) that the reduced or lost MHC I expression on tumor cells was not related to the recruitment of NK cells and the E-, L-, and P selectin that could interfere with migration of NK cells to tumor site were similar in normal mucosa and CRC. Contrary to the scarcity of NK cells in CRC, the levels of chemokines such as CXCL10, RANTES, CXCL9 were highly expressed along with high amounts of granzyme B and sCD95L which could be derived from infiltrating T cells instead. Papanikolaou et al. [109] found in CRC patients (mean age 75.9 years) a weak tissue presence of NK cells in 59.8 % of cases (n = 82) and a strong presence in 40.2 % of cases (primary tumors) whereas in metastatic lymph nodes there was 45.5 % of strong NK cell presence. It was observed a negative association between NK presence at the primary tumor site and the patients’ age but this association was not seen at the metastatic lymph nodes.

Non small-cell lung cancer (NSCLC)-infiltrating NK cells were readily detected and displayed activation markers (NKp44, CD69, HLA-DR). However, the potential of cytolysis of NK from cancer tissues was lower than from peripheral blood or normal lung whereas their capability of producing cytokines was similar [110]. Platonova et al. [111] observed that NK were enriched in NSCLC site and localized in the stroma. Cells presented a decreased expression of NKp30, NKp80, DNAM-1, CD16, and ILT2 receptors compared with NK cells from distal lung tissues or blood. Moreover, the capabilities to stimulate degranulation and IFN-y secretion were abolished in these cells in opposite to the circulating NK cells.

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