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Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells
N Kayagaki1, N Yamaguchi, M Nakayama
1Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Abstract:
TNF-related apoptosis-inducing ligand (TRAIL), a new member of TNF family, induces apoptotic cell death of various tumor cells. We recently showed that TRAIL mediates perforin- and Fas ligand (FasL)-independent cytotoxic activity of human CD4+ T cell clones. In the present study, we investigated the expression and function of TRAIL on murine lymphocytes by using newly generated anti-murine TRAIL mAbs. Although freshly isolated T, B, or NK cells did not express a detectable level of TRAIL on their surface, a remarkable level of TRAIL expression was induced preferentially on CD3- NK1.1+ NK cells after stimulation with IL-2 or IL-15. In contrast, TRAIL expression was not induced by IL-18, whereas it efficiently potentiated lymphokine-activated killer activity of NK cells. In addition to perforin inactivation and neutralization of FasL by anti-FasL mAb, neutralization of TRAIL by anti-TRAIL mAb was needed for the complete inhibition of IL-2- or IL-15-activated NK cell cytotoxicity against mouse fibrosarcoma L929 target cells, which were susceptible to both FasL and TRAIL. These results indicated preferential expression of TRAIL on IL-2- or IL-15-activated NK cells and its potential involvement in lymphokine-activated killer activity.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is preferentially expressed on activated natural killer (NK) cells. This expression contributes to lymphokine-activated killer (LAK) activity against tumor cells.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells.
- Previous studies demonstrated TRAIL-mediated cytotoxic activity independent of perforin and Fas ligand (FasL) in human T cells.
Purpose of the Study:
- To investigate the expression and function of TRAIL on murine lymphocytes.
- To determine the role of TRAIL in lymphokine-activated killer (LAK) activity of natural killer (NK) cells.
Main Methods:
- Generated anti-murine TRAIL monoclonal antibodies (mAbs).
- Analyzed TRAIL expression on lymphocytes stimulated with various cytokines (IL-2, IL-15, IL-18).
- Assessed NK cell cytotoxicity against L929 fibrosarcoma cells using neutralization assays with anti-TRAIL and anti-FasL mAbs.
Main Results:
- Freshly isolated T, B, and NK cells showed no detectable TRAIL surface expression.
- TRAIL expression was significantly induced on CD3- NK1.1+ NK cells upon stimulation with IL-2 or IL-15, but not IL-18.
- Neutralization of TRAIL, in addition to perforin inactivation and FasL blockade, was required to completely inhibit IL-2/IL-15-activated NK cell cytotoxicity against susceptible L929 target cells.
Conclusions:
- TRAIL is preferentially expressed on IL-2- or IL-15-activated murine NK cells.
- TRAIL plays a role in the lymphokine-activated killer (LAK) activity of NK cells against TRAIL- and FasL-sensitive tumor cells.