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Irreversible cancer cell-induced functional anergy and apoptosis in resting and activated NK cells
M Cavalcanti1, A Jewett, B Bonavida
1Instituto de Microbiologia Professor Paulo de Goes, Departamento de Imunologia, Federal University of Rio de Janeiro (UFRJ), Brazil.
Abstract:
The interaction of natural killer (NK) cells with target cells, such as K562, results in NK functional inactivation and apoptosis. The role of NK-activating cytokines, IL-2, IL-12, and IL-15, in the regulation of NK inactivation and programmed cell death by target cells was examined. Purified natural killer cells were obtained from human peripheral blood and either co-incubated with K562 target cells and cytokines or the NK cells were pretreated with cytokines for 18 h prior to co-culture with K562 cells. Sorted NK cells were examined for cytotoxic activity and NK co-cultured with K562 were examined for cytokine secretion, phenotyping and DNA fragmentation. The cytotoxic activity was inhibited and was not alleviated by cytokine treatment. Whereas the cytokine treatment maintained NK cell viability for several days, NK cell viability was decreased significantly in the presence of K562 target cells. Downregulation of CD16 and upregulation of CD69 on NK cells were induced by K562 target cells and no modulation of these antigens was observed with cytokine treatment. A subpopulation of target-treated NK cells succumbed to cell death by apoptosis and cell death was not rescued by the activating cytokines. These findings demonstrate that target-induced functional inactivation and apoptosis of NK cells were not rescued by the activating cytokines IL-2, IL-12, and IL-15 regardless of whether the NK cells were pretreated with cytokines prior to exposure to K562 or the cytokines were added to the NK-K562 mixtures. These results also suggest that signals triggered by the target cells and resulting in NK cell anergy and apoptosis override cytokine-mediated signals for activation, cell proliferation, and survival.
Insights
Activating cytokines IL-2, IL-12, and IL-15 do not prevent target cell-induced inactivation and apoptosis in natural killer (NK) cells. Target cell signals override cytokine-driven activation and survival pathways, leading to NK cell death.
Area of Science:
- Immunology
- Cell Biology
Background:
- Natural killer (NK) cells are crucial for innate immunity, mediating target cell lysis.
- NK cell interactions with target cells can lead to NK cell functional inactivation and apoptosis.
- NK-activating cytokines, including IL-2, IL-12, and IL-15, are known to promote NK cell activation, proliferation, and survival.
Purpose of the Study:
- To investigate the role of IL-2, IL-12, and IL-15 in regulating NK cell inactivation and apoptosis induced by target cells.
- To determine if cytokine pretreatment or co-incubation can rescue NK cells from target-induced death.
Main Methods:
- Human peripheral blood NK cells were purified and co-incubated with K562 target cells, with or without prior cytokine treatment.
- Assessed NK cell cytotoxic activity, cytokine secretion, surface antigen expression (CD16, CD69), and DNA fragmentation.
Main Results:
- Cytokine treatment did not alleviate NK cell cytotoxic activity inhibition by K562 cells.
- While cytokines maintained NK cell viability, K562 cells significantly decreased NK cell viability, inducing apoptosis.
- K562 cells induced CD16 downregulation and CD69 upregulation, effects not modulated by cytokines.
- Activating cytokines failed to rescue NK cells from target-induced apoptosis.
Conclusions:
- Target cell-induced NK cell functional inactivation and apoptosis are not rescued by IL-2, IL-12, and IL-15.
- Signals from target cells override cytokine-mediated activation and survival signals, leading to NK cell anergy and apoptosis.