Natural Killer Cells

NK cells are a subset of large granular lymphocytes that are important for the innate immune responses to viral infection and malignant transformation. NK cells express inhibitory receptors that recognize self MHC class I and thereby prevent lysis of normal cells. Virally infected cells and tumor cells that evade the MHC-restricted T-cell response by downregulating the MHC class I expression become targets for NK-medi-ated Ab-independent cytolytic killing (110,111). In humans, NK cells derive from CD34+ progenitors in the bone marrow. Mature NK cells are characteristically CD56+CD3-, tend to traffic to and concentrate in the spleen, but also represent about 10-20% of circulating lymphocytes. Approximately 90% of circulating NK cells express FcRyIII (CD16), which enables Ab-dependent cell-mediated cytotoxicity (ADCC) as an additional mechanism of target cell killing. The remaining 10% express CD56 at high density (CD56bright); are CD16-/dimc-kit+; constitutively express the high-affinity (aPyc-chains) and intermediate-affinity (aP-chains) IL-2 receptors, making them particularly responsive to IL-2 (111); and represent one of the first lymphocyte subsets to repopulate recipients of autologous or allogeneic bone marrow transplantation. Physiologically, IL-15 appears to be a critical cytokine for NK cell development

(111). IL-15 is stromal cell-derived. The IL-15 receptor complex on target cells shares homology and subunits with the IL-2 receptor complex; its a-chain is homologous to that of the IL-2 receptor complex, and its P- and yc-chains are identical to those of the IL-2 receptor complex. Importantly, the immune role of NK cells includes secretion of immunoregulatory cytokines such as IFN-y and tumor necrosis factor (TNF)-a.

In the human system, it has been shown in vitro that SCF synergistically and extensively promotes the IL-2-mediated or IL-15-mediated generation of CD5+CD3-cytolytic NK cells from bone marrow-derived (CD34+) (111,112) or fetal liver-derived (CD34+CD38+) (113) precursors; and that SCF and Flt3 ligand can each upregulate expression of the IL-15 receptor a-subunit and the IL-2/IL-15 receptor P-subunit in bone marrow-derived CD34+ cells, thereby making the cells responsive to IL-15 (111). In addition, SCF synergistically enhances the low-dose, IL-2-mediated proliferation of the CD56brightCD3-CD16-c-kit+ subset of NK cells obtained from the circulation (111). SCF alone maintains survival of this CD56bright subset in vitro, by an antiapop-totic mechanism, i.e., Bcl-2 upregulation (111).

With respect to NK cell development in mice, reduced amounts of natural killing have been noted in young W/W mice (114). In a study involving transplantation of W/W fetal liver cells to alymphoid (T-B-NK-) RAG2/yc-/- mice, NK cell reconstitution in the bone marrow and spleen was only partial (40-50%), and the reconstituted NK cells had cytolytic activity approx 50% of normal on a per cell basis, suggesting that c-kit signaling is not absolutely required for commitment to the NK lineage but is required for normal and complete NK cell proliferation and lineage maturation (91).

The ontogeny of mouse NK cells seems to parallel that in humans. In vitro, IL-7, Flt3 ligand, and (to a lesser extent) SCF enable a maturation sequence whereby c-kit+Sca-2+ Lin- bone marrow cells acquire IL-2/IL-15 receptor expression and progress to mature NK cells (NK1.1+CD3- in the mouse) upon exposure to IL-2 or IL-15 plus bone marrow-derived stroma (115). With mature splenic NK cells in vitro, SCF has been shown to decrease apoptosis and maintain viability (91). In vivo administration of SCF to normal mice for 7 d led to a 1.5-2-fold expansion of NK cellularity in the spleen and bone marrow (116), and administration of SCF with low-dose IL-2 for 8 wk led to synergistic expansion of functional NK cells in the bone marrow, spleen, and peripheral blood (three- to fourfold greater than that seen with low-dose IL-2 alone) (111).

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