Similar to other leukocyte populations, NK cells ultimately derive from hematopoietic stem cells (HSCs) that reside in the bone marrow (BM). BM-derived HSCs give rise to more committed lymphoid progenitor cells that in turn are capable of differentiating into T and B lymphocytes as well as NK cells and other non-NK ILCs.^11,12,13 The terminal aspects of human NK cell development can be divided into five stages based on the differential surface expression of CD34, CD117, CD94, CD16, and CD56 in the absence of other lineage (Lin)-specific surface markers.¹⁴ Stages 1 to 3 cells, which are lymphoid populations downstream of the HSC, do not possess cytotoxic function or the ability to produce IFN-γ, and are therefore considered immature, whereas stages 4 and 5 cells possess the aforementioned functions. Although the BM seems to be required for the development of NK cells or at least the HSC and potentially other early progenitor cells from which NK cells derive, cells belonging to stages 1 to 4 of NK cell development are enriched in locations other than the BM, such as secondary lymphoid tissue (SLT), the liver, and the uterus, suggesting that NK cell maturation occurs in extramedullary tissues. In the peripheral blood (PB), most NK cells are stage 5 cells and show a Lin⁻CD34⁻CD117⁻CD94^+/−CD16⁺CD56^dim immunophenotype. Fewer Lin⁻CD34⁻CD117^+/−CD94⁺CD16⁻CD56^bright NK cells, which correspond to stage 4 of NK cell development, are also detected in the circulation, but these are relatively much more abundant in other tissues, including SLTs.¹⁵

NK cells possess two primary effector functions: cytotoxicity and cytokine production. These functional parameters are heavily dependent on competing signals derived from activating and inhibitory receptors. There are a multitude of functional surface receptors expressed by NK cells, and these include cytokine and chemokine receptors; C-type lectin receptors such as CD94/NKG2 heterodimers, NKG2D, NKp30, NKp44, NKp46, and NKp80; killer immunoglobulin-like receptors (KIRs); and CD16 (Fc-γ receptor IIIa).^5,16 Unlike T cells, NK cells are not major histocompatibility complex (MHC)–restricted per se, yet NK cells do sense MHC class I molecule expression on other cells via NK cell expression of CD94/NKG2 and KIR molecules. MHC binding of these receptors usually results in inhibition of NK cell activity, and as such, healthy cells that express MHC class I molecules are protected from NK cell killing. In contrast, cells that have become infected or malignantly transformed may downregulate MHC class I molecules and then become susceptible to NK cell killing, especially if these cells also display pathogen-derived or stress-induced ligands on their surface that can trigger activating NK cell receptors.¹

NK cells are widely distributed throughout the body and can be found in a variety of tissues, including PB, BM, spleen, lymph nodes (LNs), liver, salivary gland, mucosa-associated lymphoid tissue (MALT), uterus, and the skin.^20,21,22 NK cells play a number of different roles, and specific tissues often have distinct resident NK cell phenotypes. Furthermore, NK cells are early responders to sites of inflammation.²² Therefore, the vascular system plays an important role in facilitating NK cells transit to the sites of the body where they are needed.