Pivotal role of endogenous TNF-alpha in the induction of functional inactivation and apoptosis in NK cells.
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.
Jewett
A
A
Department of Microbiology and Immunology, UCLA School of Medicine, University of California, Los Angeles 90095-1747, USA.
Cavalcanti
M
M
Bonavida
B
B
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*
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