**2. NK cells' biology and function**

NK cells originate from common lymphoid progenitor cells and further differentiate into immature/mature NK cells in bone marrow. They are then distributed in peripheral lymphoid and nonlymphoid organs and tissues [3–5], including bone marrow, spleen, peripheral blood, placenta, lung, liver, uterus [6], and peritoneal cavity while limited numbers are localized in lymph nodes [7]. Human NK cell turnover in blood is around 2 weeks [8].

NK cells were originally described as large granular lymphocytes with natural cytotoxicity against tumor cells. NK cells were later recognized as a separate lymphocyte lineage, with both cytotoxicity and immunoregulatory role, as they are involved in the production of cytokines [9]. More recently, data revealed that activated NK cells may also influence the outcome of helminth infections. CD4-NK cells increasing early following nematode infection with *Brugia pahangi* are able to produce IL-4 and then could polarize the immune response toward a Th2 profile [10]. In fact, protection against helminthic infections are usually mediated by Th2 immune response characterized by secretion of IL-4, IL-5, and IL-13, secretion of IgE antibodies, and activation of mast cells [11, 12]. Studies revealed that the clearance of these parasites is more efficient and complete in the presence of NK cells. In the case of Th2 immunity disruption, NK cells may become an important source of IL-13 during murine gastrointestinal nematode infections [13, 14]. Human NK cells can be classified into two major subsets CD56dim and CD56bright depending on their immunophenotype and functions and more recently in terms of their homing properties [15, 16]. CD56dim NK cells are fully mature, make up about 90% of the NK cells in peripheral blood and inflammatory sites, and they express perforin and exhibit a high cytotoxic activity after encountering target cells [17, 18]. These CD56dim NK cells are cytotoxic and produce interferon γ (IFN-γ) upon interaction with tumor cells in vitro [19]. In contrast, CD56bright cells are more immature, make up about 5–15% of total NK cells, and have been considered primarily as cytokine producers, while playing a limited role in cytolytic responses. Approximately, 90% of NK cells in lymph nodes belong to the CD56bright subset and lack perforin [20]. These cells exert immunoregulatory function by producing abundant cytokines such as IFN-γ in response to stimulation with interleukins (IL)-12, IL-15, and IL-18 [21]. In response to nematode infection, CD56bright NK cells can bind with a secreted protein ES from the human hookworm *Necator americanus* and induce IFNgamma production [22]. Natural killer cells have diverse biological functions, which include recognizing and killing pathogen-infected and cancer cells. Circulating NK cells are mostly in their resting phase, but after activation by cytokines and chemokines, they are capable of extravasation and recruitment into distinct inflamed or malignant tissues [9, 23]. NK cells also have an immunoregulatory role as their ligand interaction with cell-surface receptors lead to the production of several cytokines.

NK cells mediate two predominant pathways of cell death. The first pathway, a granule exocytosis pathway [24], involves the release of cytotoxic granule, perforin (a membrane-disrupting protein), and granzymes (a family of structurally related serine proteases) responsible for NK cell-mediated killing by inducing apoptosis of the target cell [25–27]. In the second pathway, a caspase-dependent apoptosis involves the association of death receptors such as first apoptosis signal (Fas) cell surface death receptor and tumor-necrosis-factor–related apoptosis inducing ligand receptor (TRAILR) on target cells with their corresponding ligands, members of the tumor necrosis factor (TNF) family of cytokines, expressed by NK cells, and regulated by IFN-γ, such as FASL, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), resulting in caspase-dependent target cell apoptosis [28–32]. Antibody-dependent cellular cytotoxicity (ADCC) can also be a mechanism of killing of tumor cells by NK cells by triggering the NK CD16 receptor (FcγRIII), which binds to the IgG and antibody-coated targets [33].

Natural killer cells can discriminate between normal cells and those that do not express adequate amounts of MHC class I molecules. They were originally defined by their ability to spontaneously eliminate cells lacking expression of MHC class I molecules. NK cells express receptors that bind to MHC class I molecules including the killer cell immunoglobulin-like receptors (KIRs) that play major roles in regulating the activation thresholds of NK cells in humans [34].
