**1. Introduction**

#### **1.1. Natural killer cells (NK cells)**

Natural killer (NK) cells are branded to be the native defenders of the innate immune system. NK cells are large granular cytolytic lymphocytes. They originate from hematopoietic stem cells (HSC) and undergo maturation primarily in the bone marrow (BM) [1, 2]. They constitute 2–18% of all circulating lymphocytes; they are also found in peripheral tissues like the liver, peritoneal cavity, and placenta [3, 4]. "Natural cytotoxicity" delineates an effectively contributing phenomenon of NK cells as the first resident invaders against viral infections

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and more in general against pathogens without prior sensitization [5–12]. NK cells are also involved in immune-surveillance against malignancies and prevent dissemination of metastatic tumors [13, 14]. These effector functions are mediated through cellular cytotoxicity, in addition to secretion of several chemokines and cytokines [14]. NK cells cross-talking among immune cells, as well, play a mandatory control in mediating the anti-tumor adaptive immunity of T- and B cells that contrastingly require initial priming for the expression of their activity [15, 16]. The sophisticated players of the innate immunity, NK cells exhibit distinct morphologic phenotypic and functional properties from T- and B cells [17].

#### **1.2. Human natural killer cell morphology and subsets**

Phenotypically, human NK cells are characterized by the expression of CD56 and lack of the surface marker of T cell CD3. In addition, co-expression of CD16 (FcγRIIIA, the low affinity receptor for IgG) on a majority of peripheral NK cells renders them strong mediators of antibody-dependent cellular cytotoxicity (ADCC) against IgG-coated cells [18].

Nevertheless, the non-homogenous cell compartments of NK cells divide them distinctly into two subpopulations based upon CD56 cell surface density. Accordingly, various models have been proposed regarding the phylogeny and ontogeny of these human NK cell subsets. Initially, CD56bright or CD56dim could differentiate from a common NK cell precursor, each act as separate entity. Depending on the microenvironment, inter-switching between these two subsets ranks a second possibility. Third, CD56bright may be precursors of CD56dim (or vice versa) [19, 20]. Poor understanding of their origin and the possible relationship between the subsets remains a controversy. However, each subset has distinguished functions [21, 22].

In peripheral blood, low-density expression of CD56 (CD56dim) and high expression of CD16 (CD16bright) makes up the majority (90%) of human NK cells, whereas CD56bright comprise the remaining 10% [22]. CD56bright NK cells termed as such as they express 5- to 10-fold higher level of CD56 and present either no, or at most, dim expression of CD16 [102]. By contrast, CD56bright NK cells predominate in lymph nodes and inflamed tissues [23]. Functionally, CD56dim cells represent "classical NK cells" with strong cytotoxic capacity involved with natural and AB-mediated cell cytotoxicity [20, 24, 25]. In contrast, CD56bright NK cells are characterized by enhanced cytokine production and having immune-regulatory function but poor killing properties as shown in **Figure 1** [26].

Phenotypically, CD56dim and CD56bright exhibit differential receptor profile; for example CD56dim NK cell exhibit much higher levels of KIR, whereas resting CD56bright NK cells have high expression of CD94/NKG2A. Functionally, CD56dim NK cells are essentially cytotoxic cells that produce low levels of cytokines in response to monokine stimulation. However, they are potent mediators of cytotoxic functions due to high levels of CD16 surface expression. On the other hand, CD56bright NK cells are known as immunoregulatory cells that produce high levels of cytokines such as interferon-gamma (IFN-γ), interleukin-10 (IL-10), and TGF-β upon activation. It has low expression of CD16, thus performing reduced cytotoxic functions.

Natural Killer Cells in the Near Future of Immuno-Oncological Therapeutic Approaches http://dx.doi.org/10.5772/intechopen.70567 33

Highcytokine production

and more in general against pathogens without prior sensitization [5–12]. NK cells are also involved in immune-surveillance against malignancies and prevent dissemination of metastatic tumors [13, 14]. These effector functions are mediated through cellular cytotoxicity, in addition to secretion of several chemokines and cytokines [14]. NK cells cross-talking among immune cells, as well, play a mandatory control in mediating the anti-tumor adaptive immunity of T- and B cells that contrastingly require initial priming for the expression of their activity [15, 16]. The sophisticated players of the innate immunity, NK cells exhibit distinct

Phenotypically, human NK cells are characterized by the expression of CD56 and lack of the surface marker of T cell CD3. In addition, co-expression of CD16 (FcγRIIIA, the low affinity receptor for IgG) on a majority of peripheral NK cells renders them strong mediators of

Nevertheless, the non-homogenous cell compartments of NK cells divide them distinctly into two subpopulations based upon CD56 cell surface density. Accordingly, various models have been proposed regarding the phylogeny and ontogeny of these human NK cell subsets. Initially, CD56bright or CD56dim could differentiate from a common NK cell precursor, each act as separate entity. Depending on the microenvironment, inter-switching between these two subsets ranks a second possibility. Third, CD56bright may be precursors of CD56dim (or vice versa) [19, 20]. Poor understanding of their origin and the possible relationship between the subsets remains a controversy. However, each subset has distin-

In peripheral blood, low-density expression of CD56 (CD56dim) and high expression of CD16 (CD16bright) makes up the majority (90%) of human NK cells, whereas CD56bright comprise the remaining 10% [22]. CD56bright NK cells termed as such as they express 5- to 10-fold higher level of CD56 and present either no, or at most, dim expression of CD16 [102]. By contrast, CD56bright NK cells predominate in lymph nodes and inflamed tissues [23]. Functionally, CD56dim cells represent "classical NK cells" with strong cytotoxic capacity involved with natural and AB-mediated cell cytotoxicity [20, 24, 25]. In contrast, CD56bright NK cells are characterized by enhanced cytokine production and having immune-regulatory function but poor

Phenotypically, CD56dim and CD56bright exhibit differential receptor profile; for example CD56dim NK cell exhibit much higher levels of KIR, whereas resting CD56bright NK cells have high expression of CD94/NKG2A. Functionally, CD56dim NK cells are essentially cytotoxic cells that produce low levels of cytokines in response to monokine stimulation. However, they are potent mediators of cytotoxic functions due to high levels of CD16 surface expression. On the other hand, CD56bright NK cells are known as immunoregulatory cells that produce high levels of cytokines such as interferon-gamma (IFN-γ), interleukin-10 (IL-10), and TGF-β upon activation. It has low expression of CD16, thus performing reduced cytotoxic functions.

morphologic phenotypic and functional properties from T- and B cells [17].

antibody-dependent cellular cytotoxicity (ADCC) against IgG-coated cells [18].

**1.2. Human natural killer cell morphology and subsets**

guished functions [21, 22].

32 Natural Killer Cells

killing properties as shown in **Figure 1** [26].

**Figure 1.** Human NK cell subsets differ both phenotypically and functionally.
