Ig-binding Receptors on Human NK Cells as Effector and Regulatory Surface Molecules

Sulica, Andrei; Morel, Penelope A.; Metes, Diana; Herberman, Ronald B.

doi:10.3109/08830180109054414

Cited by 61 publications

(44 citation statements)

References 117 publications

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“…The presence of the Fc portion may have caused preferential activation of macrophages and/or NK cells, because these cells express Fc␥Rs. It is also conceivable that a negative signal may have been transmitted to the immune response through the Fc␥Rs (48). It is noteworthy that all surviving mice had high levels of specific IgM that promoted C3 deposition on Meth A cells.…”

Section: Discussionmentioning

confidence: 99%

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

Ohta

Kondor

Dohi

et al. 2004

The Journal of Immunology

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Two mouse tumor cell lines, Meth A (BALB/c mouse-derived fibrosarcoma) and MM46 (C3H/He mouse-derived mammary tumor), were shown to express high levels of complement receptor-related gene y/p65 (Crry/p65), a membrane-bound complement-regulatory protein. Inhibiting the complement-regulatory activity of Crry/p65 with mAb 5D5 induced high levels of C3 deposition on in vivo tumor-derived Meth A and MM46 cells. To determine the effect of Crry/p65 blockade and increased C3 deposition on in vivo tumor growth, Meth A and MM46 cells were treated with 5D5 mAb and injected into BALB/c and C3H/He mice, respectively. Pretreating MM46 cells with 5D5 mAb significantly suppressed their tumorigenicity when injected s.c. Pretreatment with 5D5 mAb had a modest effect on Meth A s.c. tumor growth. Because complement is involved in the induction of an immune response, we investigated the effect of Crry/p65 blockade and increased C3 deposition on the immunogenicity of the tumor cells in a vaccination protocol. Vaccination of mice with irradiated Meth A cells pretreated with 5D5 mAb protected mice from subsequent challenge. In contrast, vaccination with irradiated Meth A cells without pretreatment was not protective. Survival was correlated with a high titer IgM response and specific CTL activity. These data demonstrate that the functional inhibition of Crry/p65 on tumor cells affects tumor growth and immunogenicity, and that the complement deposition resulting from this inhibition can act in concert with antitumor effector mechanisms to elicit potent antitumor immunity in vivo.

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Section: Discussionmentioning

confidence: 99%

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

Ohta

Kondor

Dohi

et al. 2004

The Journal of Immunology

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“…Furthermore, the FcgRIIIA but not FcgRIIIB binds monomeric IgG1 and IgG3 with low affinity, in a specific and saturable manner [23][24][25], and I-mIgG for 1 h at 0 C, washed and less than 7% of the total radioactivity was counted in the culture medium. Thereafter, the cells were incubated at 37 C for different time intervals and the radioactivity in the supernatant, cell pellet or elution at pH 3.0 was measured with a Well Type Gamma Counter.…”

Section: Discussionmentioning

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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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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“…Because most Fc receptor (FcR)-bearing immune cells coexpress both activating and inhibitory FcRs that bind IgG with comparable affinity and specificity, coengagement of activating and inhibitory FcRs by IgG or immune complexes usually occurs, thereby establishing thresholds for activation/repression and determining the magnitude of effector responses (10,11). The majority of NK cells, however, do not routinely express inhibitory FcRs, and thus much less is known about inhibitory signals that regulate or attenuate NK cell effector responses following FcgRIIIa engagement (12).…”

Section: Introductionmentioning

confidence: 99%

Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

Parihar¹,

Trotta²,

Roda³

et al. 2005

Cancer Research

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We have previously shown that natural killer (NK) cells secrete a distinct profile of immunomodulatory cytokines in response to dual stimulation with antibody-coated tumor cells and interleukin-12 (IL-12). This NK cell cytokine response is dependent on synergistic signals mediated by the activating receptor for the Fc portion of IgG (Fc;RIIIa) and the IL-12 receptor (IL-12R), both constitutively expressed on NK cells. The phosphatase Src homology 2-containing inositol 5V -phosphatase 1 (SHIP1) is known to exert inhibitory effects on Fc receptor (FcR) signaling via its enzymatic activity on phosphatidylinositol 3-kinase (PI3-K) products within many cells of the immune system, most notably mast cells, B cells, and monocytes. However, its activity in the context of FcR activation on NK cells has not been fully explored. The current study focused on the regulation of Fc;RIIIa-induced NK cell cytokine production by SHIP1. Inhibitor studies showed that NK cell IFN-; production following FcR stimulation in the presence of IL-12 depended, in part, on the downstream products of PI3-K. Overexpression of wild-type (WT) SHIP1, but not a catalytic-deficient mutant, via retroviral transfection of primary human NK cells, resulted in a >70% reduction of NK cell IFN-; production in response to costimulation. In addition, NK cells from SHIP1

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Ig-binding Receptors on Human NK Cells as Effector and Regulatory Surface Molecules

Cited by 61 publications

References 117 publications

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

Mouse Complement Receptor-Related Gene y/p65-Neutralized Tumor Vaccine Induces Antitumor Activity In Vivo

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‡

Src Homology 2–Containing Inositol 5′-Phosphatase 1 Negatively Regulates IFN-γ Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12

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