Pertussis toxin‐sensitive GTP‐binding proteins regulate activation‐induced apoptotic cell death of human natural killer cells
- 1 November 1995
- journal article
- research article
- Published by Wiley in European Journal of Immunology
- Vol. 25 (11) , 3094-3099
- https://doi.org/10.1002/eji.1830251116
Abstract
Apoptosis of natural killer (NK) cells can be induced by non‐specific physical damage (UV irradiation, heat shock) or by simultaneous ligation of the CD 16 and the interleukin‐2 receptor (IL‐2R) molecules, but not with either anti‐CD 16 or IL‐2 alone. Whereas blockade of GTP‐binding protein (G protein)‐mediated signal transduction using ADP‐ribosylating bacterial toxins or the GTPase‐resistant GTP analog guanosine 5′‐0‐(3‐thiotriphosphate (GTPγS) does not affect non‐specific induction of NK cell apoptosis, such interventions do inhibit induction of apoptosis by anti‐CD16/IL‐2. The G proteins involved in the regulation of activation‐induced NK apoptosis are sensitive to pertussis toxin (PTX) and to the non‐specific GTP analog GTPγS but not to cholera toxin, Pseudomonas exotoxin A or diphtheria toxin. A pertussis toxin mutant that lacks ADP‐ribosylating activity, but conserves the membrane translocating and T cell‐mitogenic effects of the native molecule, fails to inhibit NK apoptosis. To exert their apoptosis‐inhibitory effect, PTX and GTPγS must be employed before cells are activated. Later addition has no effect, suggesting the implication of G proteins in the transmission of apoptosis‐inducing signals, but not in the effector stage of apoptosis. Pre‐incubation with PTX or GTPγS does not affect the activation of NK cells by CD 16 cross‐linking, IL‐2 stimulation ‐ or both, as assessed by the induction of CD69 expression, protein tyrosine phosphorylation and calcium mobilization. Moreover, neither PTX nor GTPγS compromise the effector function of NK cells or the susceptibility of target cells to NK‐mediated lysis. These data suggest apoptosis as a novel mechanism by which NK responses may be controlled in vivo, as well as an experimental and therapeutical strategy to counteract endogenous down‐regulation of NK responses.Keywords
This publication has 33 references indexed in Scilit:
- Two-step TCRζ/CD3-CD4 and CD28 signaling in T cells: SH2/SH3 domains, protein-tyrosine and lipid kinasesImmunology Today, 1994
- Signal transduction by lymphocyte antigen receptorsCell, 1994
- Guanine nucleotide binding proteins mediate the chemotactic signal of transforming growth factor-β1 in rat IL-2 activated natural killer cellsInternational Immunology, 1993
- Molecular Regulation of the IL‐2 Gene: Rheostatic Control of the Immune SystemImmunological Reviews, 1993
- Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunityCell, 1993
- ApoptosisImmunology Today, 1993
- lnterleukin-2 programs mouse αβ T lymphocytes for apoptosisNature, 1991
- Programmed cell death and extrathymic reduction of Vβ8+CD4+ T cells in mice tolerant to Staphylococcus aureus enterotoxin BNature, 1991
- Improved method for measuring intracellular Ca++ with fluo‐3Cytometry, 1990
- G protein regulation of receptor signallingImmunology Today, 1988