title: Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, UCLA School of Medicine, University of California, Los Angeles 90095-1747, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jewett
authors.forename: M
authors.initials: M
authors.lastname: Cavalcanti
authors.forename: B
authors.initials: B
authors.lastname: Bonavida
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002352:Carrier Proteins / Q000494:pharmacology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D004915:Leukemia, Erythroblastic, Acute; D008213:Lymphocyte Activation / Q000187:drug effects; D017452:Receptors, IgG / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D017452:Receptors, IgG; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1