Target-induced inactivation and cell death by apoptosis in a subset of human NK cells

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-α and IFN-γ into the supernatant. In contrast, NKDC cytotoxic activity was enhanced by IL-2, but proliferated poorly and did not secrete TNF-α or IFN-γ 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.