The Journal of Immunology, Vol 159, Issue 10 4815-4822, Copyright © 1997 by American Association of Immunologists

ARTICLES

Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells

A Jewett, M Cavalcanti and B Bonavida
Department of Microbiology and Immunology, UCLA School of Medicine, University of California, Los Angeles 90095-1747, USA.

The interaction of purified nonactivated human NK cells with target cells overnight results in functional anergy and apoptosis in NK cells and in a change of the NK phenotype from CD16+ CD56+ CD69- to CD16(dim/- ) CD56(+/dim/-) CD69+. These studies suggested that signaling triggered by the FcR CD16 may be implicated in target cell-mediated anergy/apoptosis of NK cells. We hypothesized that triggering CD16 by anti-CD16 Ab should result in NK cells exhibiting functional and phenotypic properties similar to those obtained following triggering of NK cells with target cells. The findings demonstrate that the anti-CD16 mAb-treated NK cells acquired the CD16- CD56(+/dim) CD69+ Fas+ phenotype and lost their cytotoxic function, a significant number of the NK cells underwent apoptosis, and a selective induction of TNF- alpha synthesis and secretion was observed. The coaddition of IL-2 to anti-CD16 Ab-treated NK cells resulted in enhanced secretion of TNF- alpha and augmentation of the frequency of cell death. However, a minor subset of NK cells exhibited potent cytotoxic function and proliferated. The anti-CD16-induced effects in NK cells were largely abrogated by the addition of either anti-TNF-alpha Ab or TNF-binding protein in the cultures. There was an enhancement of NK cell killing following the addition of exogenous TNF-alpha into the culture. Cytochalasin B selectively triggered the secretion of TNF-alpha and significantly augmented the frequency of apoptosis of anti-CD16-treated NK cells. These findings demonstrate an important and pivotal role of endogenous TNF-alpha synthesis and secretion by NK cells in the induction of functional anergy and apoptosis in anti-CD16-treated NK cells.

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