Divergent Phosphotyrosine Signaling via FcγRIIIA on Human NK Cells

Manciulea, Mioara; Rabinowich, Hannah; Sulica, Andrei; Lin, Wen-chang; Whiteside, Theresa L.; DeLeo, Albert B.; Herberman, Ronald B.; Corey, Seth J.

doi:10.1006/cimm.1996.0008

Cited by 18 publications

(19 citation statements)

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“…The binding of mIgG was inhibited by F(ab 0 ) 2 fragments of 3G8 mAb, but not by anti-CD64 mAb (not shown). These data are in line with previous reports showing that NK cells do not express the high-affinity Fc IgG receptor (FcgRI/CD64) [12,[21][22][23]25]. Therefore, the binding of mIgG to our NK-cell preparation, with a purity of 95-98% CD3 -/CD14 -/CD56 þ ), occurred via FcgRIIIA.…”

Section: Discussionsupporting

confidence: 92%

“…NK cells were incubated at room temperature for 30 min, with RU36156 (30 mM) or without inhibitor. Then cells were incubated with mIgG (1 mg/5 Â 10 6 cells/ml) for 1 h at 0 C, washed and cultured for 5 min at 37 C with F(ab 0 ) 2 fragments of goat anti-human IgG [22]. NK cells (5 Â 10 6 /sample) were incubated at 4 C for 30 min with lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

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Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

Moţa¹,

Moldovan²,

Călugăru³

et al. 2004

Scand J Immunol

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Human natural killer (NK) cells express low-affinity Fc immunoglobulin G (IgG) receptor (FcgRIIIA/CD16). The binding of monomeric IgG (mIgG) and F(ab 0 ) 2 fragments of 3G8 anti-CD16 monoclonal antibody (mAb) to FcgRIIIA was investigated by flow cytometry. Over 90% of NK cells bound endogenous IgG, and during incubation at 37 C, the FcgRIIIA occupancy decreased slowly. Approximately 90% of NK cells bind mIgG or F(ab 0 ) 2 fragments of 3G8 anti-CD16 mAb. The calculated half-time (T 1/2 ) of in vitro mIgG dissociation from FcgRIIIA was 130 min. By cross-linking the mIgG ligand with F(ab 0 ) 2 fragments of anti-human IgG antibody, the T 1/2 decreases to 85 min. In kinetics study, it has been shown that 125 I-mIgG bound to FcgRIIIA is slowly released in the culture supernatant, maybe eluted at acid pH, or partially internalized and degraded. The binding of IgG to FcgRIIIA was increased by 53.8% on cells cultured in the presence of RU36156, a matrix metalloproteinase (MMP) inhibitor. Furthermore, an increase in phosphorylation of Lyn tyrosine kinase, after cross-linking of mIgG-FcgRIIIA complex, was observed on NK cells treated with RU36156. When the FcgRIIIA was occupied by mIgG, the capacity of NK cells to kill K562 target cells was decreased by RU36156, because the MMP inhibitor protects CD16 from proteolysis. Our data demonstrate that binding of mIgG to human NK cells is followed by ligand dissociation and/or internalization, enzymatic degradation and exocytosis. The RU36156 MMP inhibitor protects FcgRIIIA from cleavage, augments NK-cell activation and may interfere in their killing capacity.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

Moţa¹,

Moldovan²,

Călugăru³

et al. 2004

Scand J Immunol

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“…Fc␥RIIIa is known to signal through the Ras-MAPK pathway (31,32), and IL-21 has been shown to activate the p44/42 MAPK Erk in a promyelocytic cell line (33). Studies in which NK cells were pretreated with chemical inhibitors of specific signal transduction pathways indicated that NK cell IFN-␥ secretion in response to IL-21 and immobilized IgG is dependent on activated Erk.…”

Section: Il-21 Enhances the Efficacy Of An Antitumor Mab In A Murine mentioning

confidence: 99%

Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets

Roda

Parihar

Lehman

et al. 2006

The Journal of Immunology

111

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NK cells express an activating FcR (FcγRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-γ secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-γ. Increased secretion of TNF-α and the chemokines IL-8, MIP-1α, and RANTES was also observed under these conditions. NK cell IFN-γ production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-γ by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-γ. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.

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“…The presence of Fc § R was previously reported on a subpopulation of T and B cells [2], monocytes and macrophages (M ¶ ) [3,4], neutrophils and eosinophils [5,6], and recently on a subset of human DC [7]. On NK cell surface, Fc + RIIIa [8,9], Fc + RIIc [10] and Fc ? R [11,12] were demonstrated previously, and human IgG and IgM were capable of negative regulation of NK activity [10,11].…”

Section: Introductionmentioning

confidence: 95%

“…Furthermore, interaction between Fc + RIIIa and Fc ? R of NK cells and their physiological ligands trigger the activation of different Src family kinases and Syk-related tyrosine kinases, which are associated with members of the receptor complex [9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Human NK cells express Fc receptors for IgA which mediate signal transduction and target cell killing

Moţa¹,

Manciulea²,

Cosma³

et al. 2003

Eur J Immunol

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Divergent Phosphotyrosine Signaling via FcγRIIIA on Human NK Cells

Cited by 18 publications

References 0 publications

Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

Interaction of Human Immunoglobulin G with CD16 on Natural Killer Cells: Ligand Clearance, FcγRIIIA Turnover and Effects of Metalloproteinases on FcγRIIIA‐Mediated Binding, Signal Transduction and Killing‡

Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets

Human NK cells express Fc receptors for IgA which mediate signal transduction and target cell killing

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