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Target-induced inactivation and cell death by apoptosis in a subset of human NK cells
1Department of Microbiology and Immunology, UCLA School of Medicine, University of California at Los Angeles 90095, USA.
Abstract:
Interaction of sensitive target cells with NK cells results in both positive and negative signaling. Positive signaling results in the induction of NK cytotoxicity and sensitization for IL-2-mediated proliferation and secretion of cytokines. Negative signaling prevents the NK cells from recycling for cytotoxicity. Functional inactivation is restricted to the NK-target conjugate subset sparing the nonconjugating free NK subset. The mechanism of target-induced inactivation of NK cells was examined in cell-sorted and purified conjugates. The conjugates were subdivided into two fractions; in one fraction the NK cells were dissociated from the target (NKDC), and in the other fraction the conjugates were not disturbed (NKC). After coculture overnight with IL-2, the cytotoxic function of NKC was not augmented although a subpopulation proliferated and secreted TNF-alpha and IFN-gamma into the supernatant. In contrast, NKDC cytotoxic activity was enhanced by IL-2, but proliferated poorly and did not secrete TNF-alpha or IFN-gamma following IL-2 activation. The phenotype of the inactive NKC was found to be CD16dim/- CD692+ CD11b2+. Target-mediated inactivation correlated with target cell sensitivity to NK cytotoxicity. Furthermore, a significant fraction of NK cells in the NKC was programmed for cell death by apoptosis. Altogether, these results demonstrate that sensitive targets inactivate NK cells for cytotoxicity resulting in loss of NK cells. Furthermore, the results suggest that signaling for cytotoxic function by target cells is not linked to signaling for proliferation and secretion of cytokines by NK cells.
Insights
Sensitive target cells induce negative signaling in natural killer (NK) cells, leading to NK cell inactivation and apoptosis. This target-induced NK cell dysfunction impairs cytotoxicity, distinct from proliferation and cytokine secretion signals.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for innate immunity, mediating cytotoxicity against target cells.
- NK cell activity is regulated by a balance of activating and inhibitory signals.
- Target cell interactions can induce both positive and negative signaling in NK cells.
Purpose of the Study:
- To investigate the mechanism of target-induced inactivation of NK cells.
- To differentiate the signaling pathways for NK cell cytotoxicity versus proliferation and cytokine secretion.
- To analyze the phenotype and fate of NK cells interacting with sensitive targets.
Main Methods:
- Isolation and purification of NK cell-target conjugates (NKC) and dissociated NK cells (NKDC).
- Coculture of NKC and NKDC with IL-2, followed by assessment of cytotoxic function, proliferation, and cytokine secretion (TNF-alpha, IFN-gamma).
- Phenotypic analysis (CD16, CD69, CD11b) and apoptosis assessment of NK cells.
Main Results:
- Target-induced inactivation was restricted to conjugated NK cells (NKC), sparing free NK cells (NKDC).
- IL-2 enhanced NKDC cytotoxicity but not NKC; NKC showed limited proliferation and cytokine secretion.
- Inactive NKC exhibited a CD16dim/- CD692+ CD11b2+ phenotype and increased apoptosis, correlating with target sensitivity.
Conclusions:
- Sensitive target cells actively inactivate NK cells, leading to functional loss and apoptosis.
- Signaling for NK cell cytotoxicity is distinct from signaling for proliferation and cytokine release.
- Target-mediated NK cell inactivation represents a critical mechanism of immune evasion.