Natural Killer (NK) Cell–mediated Cytotoxicity: Differential Use of  TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells

Abstract

Mature natural killer (NK) cells use Ca2+-dependent granule exocytosis and release of cytotoxic proteins, Fas ligand (FasL), and membrane-bound or secreted cytokines (tumor necrosis factor [TNF]-α) to induce target cell death. Fas belongs to the TNF receptor family of molecules, containing a conserved intracytoplasmic “death domain” that indirectly activates the caspase enzymatic cascade and ultimately apoptotic mechanisms in numerous cell types. Two additional members of this family, DR4 and DR5, transduce apoptotic signals upon binding soluble TNF-related apoptosis-inducing ligand (TRAIL) that, like FasL, belongs to the growing TNF family of molecules. Here, we report that TRAIL produced or expressed by different populations of primary human NK cells is functional, and represents a marker of differentiation or activation of these, and possibly other, cytotoxic leukocytes. During differentiation NK cells, sequentially and differentially, use distinct members of the TNF family or granule exocytosis to mediate target cell death. Phenotypically immature CD161+/CD56− NK cells mediate TRAIL-dependent but not FasL- or granule release–dependent cytotoxicity, whereas mature CD56+ NK cells mediate the latter two.

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

“…Notably, TRAIL is expressed on a variety of cells involved in host defense against viral infection including cytotoxic T cells, 9,10 dendritic cells, 11 monocytes/macrophages 12 and natural killer (NK) cells. 13,14 Not surprisingly, viruses have developed sophisticated strategies to both exploit TRAIL's potent cytotoxic properties, and to modulate cellular responses to TRAIL. For example, infection with human immunodeficiency virus-1 (HIV-1) can trigger the expression of TRAIL in monocytes, contributing to HIV-1 pathogenesis by inducing CD4( þ ) T-cell death.…”

NK Cells and Cancer

“…More in general, NK cells can be activated by various stimuli such as contact with dendritic cells (DC), MHC-I-negative cells, binding of IgG immunocomplexes, direct engagement of NKR by stress-induced tumor-associated molecules or pathogen-derived products, and several cytokines such as IL-1, IL-2, IL-12, IL-15, IL-18, IL-21, and type I IFNs (8 -25). Upon cytokine stimulation, NK cells become lymphokine-activated killer (LAK) cells that proliferate, produce cytokines, and upregulate effector molecules such as adhesion molecules, NKp44, perforin, granzymes, Fas ligand (FasL), and TRAIL (8,9,12,(25)(26)(27)(28)(29). Thanks to this new pattern of protein expression, LAK cells enhance their ability to adhere to and recognize target cells, leading to a broader killing activity against tumor cells that essentially takes place as (30): 1) perforin/granzyme-dependent necrosis of target cells, involving cell adhesion, NKR triggering, and granule release (31,32); and 2) apoptosis of target cells, which involves cell adhesion and is mediated by surface TNF ligand family members a) FasL, b) TNF-␣, and c) TRAIL, each of which interacts with specific receptors on the target cell surface (26 -29).…”

“…Increased incidence of primary tumors and metastases has been described in TRAILdeficient mice (35). However, TRAIL is present in the bone marrow, a site of NK cell as well as erythromyeloid differentiation (29,36). Since it has been demonstrated that erythroid cell differentiation is negatively regulated in vitro and in vivo by recombinant TRAIL (36 -38), its use in therapy should be cautious.…”

Effect of bevacizumab plus XELOX (CapeOX) chemotherapy on liver natural killer cell activity in colorectal cancer with resectable liver metastasis

“…Proportion of TRAIL‐positive NK cells significantly increased in LMNC from group B compared with that from group A ( P = 0.03; Figure 2D). Reportedly, TRAIL can induce either apoptosis by Fas‐associated death domain‐dependent mechanism or necrosis through receptor‐interactive peptide‐dependent cascade through the ligation of its death domain‐containing receptors under physiological conditions 28. MFI of NKp46 and CD122, known as IL‐2Rβ, on liver NK cells was significantly higher in group B than in group A ( P = 0.04 and P = 0.03, respectively; Figure 2C).…”