Natural killer (NK) cells comprise approximately 5–15% of peripheral blood lymphocytes. They originate in the bone marrow from CD34+ hematopoietic progenitor cells,1 although recent studies suggest that NK cell development also occurs in secondary lymphoid tissues2 and in the thymus.3
NK cells populate different peripheral lymphoid and non-lymphoid organs, including lymph nodes, thymus, tonsils, spleen, and uterus.3,4 These innate effector cells specialize in killing tumor and virally infected cells and are able to secrete a variety of cytokines.5,6 In the peripheral blood, there are two NK subpopulations. The CD56dim CD16+ NK cells, which comprise ∼90% of the NK population, are considered to be more cytotoxic than the CD56bright CD16− NK cells, which comprise only ∼10% of peripheral blood NK cells and are the primary source of NK-derived immunoregulatory cytokines, such as interferon-γ (IFN-γ), tumor necrosis factor (TNF)-β, interleukin (IL)-10, IL-13, and granulocyte–macrophage colony-stimulating factor (GM-CSF).7 Although, a recent report suggests that even the CD56dim CD16+ NK population could secrete a large amount of cytokines, especially when interacting with target cells.8 These two NK subsets also differ in the expression of NK receptors, chemokine receptors and adhesion molecules, and in their proliferative response to IL-2. For example, CD56dim NK cells express high levels of the killer cell Ig-like receptors (KIRs) and CD57,9 whereas most of the CD56bright NK cells do not express KIRs and CD57, but express high levels of CD94/NKG2 receptors.10 The differential expression of chemokine receptors and adhesion molecules can also account for the functional differences between these NK subsets. For example, CD56bright NK cells express high levels of CCR7, CXCR3, and CXCR4.7,11 In addition, they express high levels of the adhesion molecule l-selectin.7 The expression of these molecules implies that CD56bright NK cells can migrate to secondary lymphoid organs, as well as to non-lymphoid organs. Indeed, it was shown that the T-cell regions of lymph nodes are enriched with CD56bright NK cells.12 It was also demonstrated that non-lymphoid tissues, such as the decidua, are enriched with this NK subset,11 which will be discussed later.
CD56dim NK cells, on the other hand, lack the expression of these molecules, but express high levels of the chemokine receptors CXCR1 and CX3CR1, which are linked to lymphocyte migration to peripheral inflammatory sites. One of the most prominent differences between the CD56bright and the CD56dim NK subsets is their intrinsic cytotoxic capabilities. As mentioned above, resting CD56dim NK cells are much more cytotoxic than resting CD56bright NK cells.7 The molecular mechanisms responsible for this are not fully understood. CD56dim NK cells are more granular than CD56bright NK cells13 and differences in the intracellular signaling pathways between the two subsets may also account for their cytotoxic capabilities. Indeed, it was demonstrated by gene expression profiling that compared with CD56dim NK cells, CD56bright NK cells express lower levels of the CD3ζ adaptor molecule, which mediates some of the natural cytotoxicity receptor signaling.14
Importantly, CD56dim NK cells exhibit high expression levels of FcγRIII (CD16), whereas CD56bright NK cells do not express CD16 or express only low levels of it and therefore, cannot perform antibody-dependent cellular cytotoxicity (ADCC). CD16 is a unique receptor not only because of its late function when the adaptive immune response is already activated, but also because among almost all NK cell receptors tested, it is the only receptor that could function independently without the help of other NK cell receptors.8