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Target-cell-induced anergy in natural killer cells: suppression of cytotoxic function
1Centre for Cellular and Molecular Biology, Hyderabad, India.
Abstract:
Our earlier studies have demonstrated that natural killer (NK) cells are the effectors that participate during the spontaneous regression of AK-5 tumour in syngeneic hosts. We have shown that the tumour cells are killed by necrosis and apoptosis. In this study, we have examined the induction of functional anergy in NK cells following coculture with fixed AK-5 tumour cells at high ratio. NK cells, upon coculture with fixed AK-5 cells (1:1 ratio), showed loss of cytotoxic function against both AK-5 (antibody-dependent cell cytotoxicity) as well as YAC-1 targets. The response of these cells to the activation by recombinant interleukin-2 and recombinant interferon gamma was poor. Induction of tumour necrosis factor alpha (TNFalpha) secretion was observed after coculture of NK cells with fixed AK-5 cells. The cocultured cell supernatant inhibited the cytotoxic activity of NK cells, which was partially restored with anti-TNFalpha antibody. In addition, NK cells, after treatment with fixed tumour cells showed overexpression of the Fas receptor. We have also observed induction of apoptosis in cocultured NK cells. These studies suggest that the fixed tumour cells (antigen) at high ratio are able to suppress NK cell function as well as induce death in NK cells.
Insights
High tumor cell ratios induce functional anergy and apoptosis in natural killer (NK) cells. This suppression of NK cell activity is partly mediated by tumor necrosis factor alpha (TNFalpha).
Area of Science:
- Immunology
- Cancer Biology
- Cellular Immunology
Background:
- Natural killer (NK) cells are crucial for spontaneous tumor regression.
- NK cells eliminate tumor cells via necrosis and apoptosis.
- Previous studies identified NK cells as effectors in AK-5 tumor regression.
Purpose of the Study:
- To investigate the induction of functional anergy in NK cells upon co-culture with fixed AK-5 tumor cells.
- To elucidate the mechanisms underlying NK cell dysfunction and death in the presence of tumor antigens.
Main Methods:
- Co-culture of NK cells with fixed AK-5 tumor cells at a 1:1 ratio.
- Assessment of NK cell cytotoxic function against AK-5 and YAC-1 targets.
- Evaluation of NK cell response to recombinant interleukin-2 and interferon-gamma.
- Measurement of tumor necrosis factor alpha (TNFalpha) secretion.
- Analysis of Fas receptor expression and NK cell apoptosis.
Main Results:
- Co-culture with fixed AK-5 cells induced loss of NK cell cytotoxic function (antibody-dependent cell cytotoxicity).
- NK cells exhibited poor responses to IL-2 and IFN-gamma activation.
- Tumor necrosis factor alpha (TNFalpha) secretion was induced, and its antibody partially restored NK cell activity.
- Overexpression of Fas receptor and induction of apoptosis were observed in NK cells.
Conclusions:
- Fixed tumor cells at high ratios suppress NK cell function, leading to anergy.
- NK cell death is induced through apoptosis, partly mediated by TNFalpha.
- Tumor antigens can actively inhibit the host's anti-tumor immune response via NK cell suppression.