Fc receptors (FcR) ()bind the Fc region of immunoglobulin G (IgG) and are expressed on the surface of a variety of cells. The human high affinity FcR (FcRI) is a multichain receptor comprised of a 70-kDa glycoprotein -chain and homodimeric largely intracellular -chain subunits(1, 2) . Surface expression of the receptor on monocytes and U937 cells is induced by IFN-(3, 4, 5) . FcRI binds with high affinity (K= 3 nM) human IgG subclasses IgG1 and IgG3. It has one log less affinity for IgG4 and no apparent affinity for IgG2(6, 7) . The receptor binds with high affinity certain IgGs from other species that possess sequence homologies in the C2 Fc regions(6) . FcRI engagement of complexed IgG or anti-receptor antibodies(8, 9) aggregates the receptor(10, 11) , triggering several very early responses including fluxes of intracellular Ca(12, 13) , tyrosine phosphorylations of several proteins (14) and activation of the NADPH oxidase pathway(12) .

Myelocytic signaling functions of FcRI, FcRIIIA, FcRI, and FcR (15) are mediated by tyrosine activation of -chains (10, 11, 13) in motifs recognized by members of src family(16) . Src kinases Hck and Lyn associate with FcRI -chains to constitute a preaggregation multichain transduction unit(17) . Aggregation of FcRI induces the tyrosine phosphorylation of its -chains(15, 18) and the tyrosine phosphorylation of Syk kinase(18, 19, 20) . Syk, a 72-kDa structural homologue of the T-cell signal-transducing ZAP70, is recruited to -chains on activated FcRI(21) .

We have previously reported that an equimolar mixture of anti-FcRI monoclonal antibodies 32 and 22 is a potent combination for triggering FcRI-mediated NADPH oxidase activity(8, 9) . Subsequently, we found that the F(ab`) fragments of these anti-FcRI trigger poorly, and that this situation is reversed by binding high affinity IgG to the receptors(22) . For this report, we analyzed the consequences of IgG-binding on signaling through FcRI. By engaging the ligand binding site on FcRI with monomer ligand and then cross-linking the receptors through anti-FcRI F(ab`), we show evidence of a novel dependence on IgG-Fc for FcRI transductional activity. We show that IgG-Fc binding increased aggregation-dependent O production, tyrosine phosphorylation of FcRI -chains, and the association of pp72Syk kinase to activated FcRI.

MATERIALS AND METHODS

Cells

Antibodies and Immunoglobulins

Figure 2: Effects of Igs of various species, class, and subclass on FcRI signaling. Cells were preincubated in various Igs and, after a brief wash, were analyzed for the percent occupancy of FcRI-ligand binding sites and for FcRI-mediated O production. A, preincubations contained hIgG1 (H), goat IgG (G), rabbit IgG (R) (10 µg/ml), or medium (none). B, preincubation media were hybridoma supernatants (200 µl) containing murine (m) or rat (r) mAbs of IgG subclasses 2a (2a), 1 (1), and 2b (2b) or of the IgM (M), A (A), or E (E) classes. Identities of mAbs are listed under ``Materials and Methods''; those with reactivity toward monocyte surface antigens are indicated (*). Assays of mAb-preincubated cells included control cells preincubated with hIgG1 or medium. In B, the O production by cells receiving 32F(ab`) and 22F(ab`) but no IgG was subtracted. Therefore, data in B represent the enhancement of O production due to ligand. (Negative values are slight depressions in response by unligated receptors.)

Assay for O Production

FACS Analysis of Cell-associated Antibodies and Ligands

Aggregation and Internalization

Immunoprecipitation, Immunoblotting, and Autoradiography

RESULTS

IgG-Fc Binding Increases FcRI-mediated Signaling

Figure 1: The effect of hIgG on FcRI-mediated O production. A, U937 10.6 cells, differentiated by IFN- for 6 days, were preincubated for 10 min in O assay medium with and without hIgG1 (G1) (10 µg/ml). IV.3Fab (25 µg/ml) was added to block FcRII. The preincubated cells were added to luminol containing 32F(ab`) and 22F(ab`) (F) (5 µg/ml each), or 22F(ab`) alone as control. O production was measured by luminometry and is expressed in mV ± S.D. Controls were subtracted. B, human monocytes cultured with IFN- for 2 days were preincubated with or without hIgG1 for 5 min and stimulated by the addition of cells to luminol containing 5 µg/ml intact mAbs 32 and 22 (W) or 32F(ab`) and 22F(ab`) (F). C, U937 10.6 cells were preincubated with human IgG subclasses 1, 2, 3, and 4, or no IgG (none) for 10 min and then washed. Duplicate cell samples were stimulated by the addition of 32F(ab`) and 22F(ab`) for an O assay. Another set of duplicates were incubated with FITC-hIgG1 and analyzed by FACS to measure hIgG subclass binding. O production and IgG-binding to FcR are expressed as a percent of the hIgG1 control. There was no detectable binding by hIgG2. Data represent the mean of three experiments.

A similar assay was performed with monocytes that were treated with IFN- to induce the surface expression of newly synthesized FcRI. Treatment was done in culture medium lacking IgG so that induced receptors would be occupied by high affinity ligands. When anti-FcRI F(ab`) triggered receptors in the absence of IgG, there was almost no activity (Fig. 1B), but monocytes that had been preincubated with IgG produced a respiratory burst that was comparable with that triggered by intact anti-FcRI. We conclude that IgG binding profoundly affected FcRI signaling in normal human receptors.

To determine whether other human subclasses exert a similar effect, we preincubated 10.6 cells with hIgG subclasses 1, 2, 3, and 4; washed the cells briefly; and then cross-linked their FcRI. As shown in Fig. 1C, hIgG1- and hIgG3-preincubated cells had enhanced FcRI signaling, whereas hIgG4 preincubation produced an intermediate response. FACS analysis showed that bound IgG-binding to the cells (Fig. 1C) correlated with enhanced O production (Fig. 1C). HIgG2 did not bind and had no effect on signaling over the IgG-free control.

Certain other nonhuman IgGs bind human FcRI. To analyze their effect specifically on FcRI signaling, we tested cells after exposure to several murine and rat mAbs of various Ig classes and subclasses as well as rabbit and goat polyclonal IgGs. As shown in Fig. 2A, rabbit IgG, which binds with high affinity to FcRI, supported signaling to the same extent as did hIgG1, whereas goat IgG neither bound nor affected response above the control. As shown in Fig. 2B, murine IgG2a and rat IgG2b mAbs are the subclasses that bind to FcRI, whereas murine mAbs of the IgA, IgE, and IgM classes, murine IgG1 and IgG2b mAbs, and rat IgG2a mAbs bind poorly or not at all. As shown, only the mAbs that bound enhanced O production through FcRI. Some mAbs had antigen specificities for non-FcRI monocyte epitopes, but these had no apparent affect on O production attributable to antigen (Fig. 2A, asterisks). Some exceptions were mIgG1 mAbs that recognize leukocyte function-associated antigens and an IgE mAb. These mAbs reduced FcRI-binding sites without affecting O production. Overall, the results suggest that ligand occupancy by high affinity IgG enhanced FcRI-signaling for the oxidative burst.

Ligand-bound Structure

Figure 3: Hybrid Abs enhance FcRI-mediated signaling. Cells were preincubated for 10 min with hIgG1 or hybrid murine mAbs comprising two IgG2a chains (2a/2a), one IgG2a and one IgG2b chain (2a/2b), or one IgG2a and one IgG1 chain (2a/1) (7 µg/ml each). Anti-FcRI F(ab`) were added as in Fig. 2, and FcRI-mediated O production was measured. The preincubations and assay were repeated in the presence of 25 µg/ml IV.3Fab. Data are expressed as a percent of the hIgG1 control.

The effect of hybrids suggested a ligated structure involving one receptor/IgG as opposed to a trimer composed of two receptors each binding to one heavy chain on IgG. For a more direct approach in establishing this ratio, we measured cell-associated 32, 32Fab, and 32F(ab`), to establish the number of FcRI on cells; we measured cell-associated IgG2a, to establish the number of ligand binding sites/cell. The results of a FACS analysis (Table 1) show that IgG-binding sites equal the number of FcRI, indicating that the ligated structure must have a ratio of one FcRI/bound IgG.

IgG-binding Does Not Prime Cells or Increase FcRI Expression

Figure 4: Effect of IgG on the fMLP-triggered respiratory burst. Cells were preincubated with medium (med), hIgG1, 32F(ab`), or hIgG1 plus 32F(ab`). They received 22F(ab`) to trigger FcRI or fMLP (5 10M) to stimulate chemotactic receptors. O production is expressed in mV.

Measurements by FACS analysis of the number of surface FcRI following a typical preincubation of cells with IgG revealed no significant increase in FcRI numbers (Table 2). Thus, neither cell-priming nor increased numbers of surface FcRI account for the increase in signaling.

Enhanced FcRI Signaling Is Not Due to a Specific Mode of Anti-FcRI Binding

Second, the possibility that ligation might increase signaling through an increased rate of anti-FcRI binding was tested. Rates of binding depend on concentrations of the anti-FcRI antibodies(8, 9) . Since there is a linear relationship between the rates of binding of cross-linking antibody and O generation(8, 9) , times of peak rates of response correspond to peak rates of binding. Therefore, peak times could be used as an index for the rate of binding. As shown in Table 4, peak times were changed by antibody concentration but not by IgG-ligation.

Third, FcRI were aggregated through anti-FcRI F(ab`) plus sheep or goat anti-murine antibodies, or through 22Fab covalently conjugated multimers that cross-link FcRI and would have a different gross physical structure compared with 22F(ab`). In each case, ligand-increased signaling was found (Table 5). These data show that enhancement was not due to a unique mode of bridging by 22F(ab`). Collectively, the results indicate that enhancement was not due to a specific mode of anti-FcRI binding.

Cross-linking of Unligated FcRI Induces Receptor Aggregation and Internalization

IgG Predisposes FcRI for Aggregation-dependent Signaling

Figure 5: IgG-binding prior to FcR-cross-linking produces the critical change in transductional activity. A, cells were preincubated with hIgG1 and 22F(ab`), and individual samples of these cells were given 32F(ab`) at 0, 3, 6, 9, or 12 min to stimulate O production. One sample received no 32F(ab`) (none). B, cells were preincubated in 22F(ab`) for 10 min, and stimulated by the addition of 32F(ab`). HIgG1 was added to individual samples of these cells at 0, 3, 6, 9, or 12 min, or no hIgG1 was added (none). Results are presented as rate of O production, measured in mV/s and expressed as a percent of the optimum.

Dose Response of FcRI/IgG in Aggregates

Figure 6: Effect of IgG concentration on aggregation-dependent FcRI signaling. In sequential experiments, cells were preincubated in O assay medium containing 0, 0.06, 0.125, 0.25, 0.5, 1, 2, and 4 µg/ml hIgG1 (opencircles) or 0.7, 7, 23, 70, 230, and 7000 µg/ml hIgG1 (filledcircles). Samples in each were assayed for FcR-mediated respiratory bursts (A) and hIgG1-binding (B). B was measured by FACS analysis following an incubation with FITC-conjugated anti-hIgG antibody; data is expressed as the mean fluorescence intensity of cells. C, data were calculated from results in A and B to determine O production as a function of hIgG1-binding. On a log plot, data falls on a straight line indicating that O production/ligated receptor decreases by a simple exponential function (not shown). The saturation (SAT'N) point for IgG1-binding is indicated by an arrow. Data represent the mean ± the half-range of seven assays.

Phosphorylation of FcRI -Chains and Association of Syk

()

Figure 7: Effect of IgG on -chain phosphorylation and the co-precipitation of pp72Syk. A, cells preincubated with or without hIgG1 were incubated in O assay medium containing 22F(ab`) or 22F(ab`) and 32F(ab`). After 5 min at 37 °C, the cells were centrifuged through cold PBS/100 uM NaVO (1 ml) and solubilized in digitonin lysis buffer. The receptors were precipitated by GAMk-AB1 beads, separated by nonreducing SDS-polyacrylamide gel electrophoresis, transferred, and analyzed by immunoblot using anti-phosphotyrosine (anti-PY). The membrane was stripped and reblotted with anti--chain (anti-) antibody. Blots were developed using horseradish peroxidase-conjugated second antibody and ECL. Phospho-2 is indicated by brackets. The anti--reactive 18-22-kDa proteins beneath phospho- are unphosphorylated -chain dimers. Arrow indicates pp72. B, anti-PY and anti-Syk immunoblots of 72-kDa proteins that co-precipitated with cross-linked FcRI.

DISCUSSION

In this report, we demonstrate that signaling resulting in activation of the NADPH oxidase pathway and involving the tyrosine phosphorylation of -chains on FcRI is markedly increased by IgG-Fc interaction with the receptor ligand binding site. To show the effect on FcRI-mediated NADPH oxidase activity, we triggered through FcRI on monocytic cells exposed to a variety of IgGs and found that all IgGs that bound to IFN--treated U937-10.6 monocytic cells, including rabbit, human subclasses 1 and 3, murine subclass 2a, and rat subclass 2b, increased the FcRI-mediated production of O. Low affinity IgGs and IgA, IgM, and IgE had no effect. Binding to some leukocyte integrins caused slight FcRI blocking but did not increase FcRI signaling.

Significantly, binding by IgG had a direct effect on the receptor in that it increased the aggregation-dependent tyrosine phosphorylation of FcRI -chains(15, 18) . This was accompanied by the binding to activated FcRI of a 72-kDa tyrosine phosphoprotein, identified as pp72Syk. This result is consistent with recent studies showing that Syk binds to tyrosine phosphorylated -chains in cells stimulated through FcRI(18) , to -chains in activated FcRI complexes(21, 32) , and to homologous tyrosine-phosphorylated motifs in activated B-cell receptor complexes(33) . We propose that IgG-binding creates a change in availability of FcRI -chains that permits aggregation-dependent tyrosine phosphorylation of -chain motifs and recruitment of pp72Syk. Another possibility is that ligand binding influences the affinity of the -subunits for associated Src kinases (17) , perhaps modifying the kinetics of reactions in aggregates.

This study also shows a correlation between -phosphorylation, pp72Syk association, and O production, suggesting a link between FcRI-associated tyrosine kinases and the activation of the NADPH oxidase pathway.

Experiments to elucide possible effects of IgG other than on signaling through FcRI demonstrated that enhancement was not due to global cell-priming, because triggering through fMLP was unaffected. It was not due to an increase in the numbers of surface FcRI nor to specific modes of cross-linking by anti-FcRI antibodies. It was also not due to a lack of aggregability of unligated FcRI. These negative results help to support the proposed hypothesis that aggregation without ligand is transductionally insufficient.

The IFN--induced receptors on U937-10.6 cells appeared somewhat less IgG-Fc-dependent than those on monocytes. However, induced receptors on premonocytic U937 cells were not tested after a comparable expression time because several days of additional culture are required to develop an oxidative capacity in the tumor cells(23) . Furthermore, greater numbers of FcRI are expressed through induction on the U937-10.6 subclone. Thus, age or number (or some other factor) could have converted a minority of receptors to what may be an easily achieved signal-efficient configuration. Regardless of the reason, characterizing newly expressed normal monocyte FcRI as IgG-Fc-dependent strengthens our conclusions on the importance of Fc to FcRI signaling.

The nature of the improved signaling is not yet understood. However, several observations were made that partially characterize the ligand/receptor relationship. (i) IgG that was bound to cells was not itself cross-linked, making it unlikely that a mechanical strain altered the receptor and more likely that the interaction with IgG-Fc perse brought about relevant changes. (ii) Concentrations of IgG optimizing transductional activity were identical to those saturating FcRI, supporting the biochemical linkage and the specificity of the reaction. (iii) This interaction in unaggregated, signal-quiescent FcRI did not increase phosphorylation of . Therefore, potentiation was not accompanied by an obvious increase in activity of protein-tyrosine kinases associating with -chains(17) . However, binding could have increased protein-tyrosine kinase affinity, a point presently under investigation. (iv) When ligand was bound after receptor cross-linking, there was no return to oxidase activation. This outcome is consistant with the view that, with or without ligand, aggregation provides only a transient opportunity (interval/receptor) for transductional activity (8, 9) and that the ligand is effecting a change within this window. (v) At various subsaturating IgG concentrations, anti-FcRI cross-linking must have produced mixed aggregates of ligated and unligated FcRI, and in these cases, O production decreased exponentially with the decrease in ligand-occupied receptors (Fig. 6C). Evidently, the unligated receptors were not only refractory as triggers but seemed obstructive to efficient signaling. The surprising implication is that the alteration in ligated FcRI seems not to have been transmitted to proximate unligated FcRI. If the alteration were a matter of affinity or availability of Src kinases on -chains, it is possible that the kinase concentration was diluted below a critical level for a trans-activation of the unligated FcRI. In any case, this evidence indicates that ligated and unligated FcRI are markedly different in ways that are critical and specific to transductional activity.

A further characterization using hybrid antibodies indicated that signal-enhancement was achieved through the binding of IgG containing only one high affinity heavy chain capable of binding FcRI. This evidence alone would not have excluded the possibility of hybrid low affinity chain engagement of a second FcRI or an FcRII. However, we made direct measurements that show that the potentiated FcRI structure has a ratio of one receptor/hIgG1 ligand. This indicated that the other heavy chain on hIgG1 does not engage with high affinity the ligand-binding site on a second FcRI. Additionally, measured with IV.3Fab as a block, the second heavy chain does not occupy the ligand binding site on FcRII. Therefore, as predicted by the hybrids, only one of the two heavy chains of IgG binds in a manner sufficient for potentiation. Unlike the ligand-induced dimerization characteristic of several cytokine receptor family members(34) , monomer ligand does not dimerize FcRI.

The results of this study do not alter the general view that aggregation, not a ligand-induced physical change in FcR, is the key event in transmembrane signaling(35) . But in addition to that, IgG-Fc binding must alter FcRI such that those events normally involved in aggregation-dependent signal transduction can occur. It is our speculation on this point that Fc binding stabilizes an activatable configuration of the receptor, one that may be present to varying extents in the nonphysiologic conditions of ligand-free cell culture. Fc region involvement other than in passive mediation of myelocytic antigen recognition has been suggested by Brown and Koshland(36, 37) , and some distinctions in FcR-mediated cytotoxicity due to hIgG-Fc in subclasses 1 and 3 have also been described(38, 39) . Physicochemical studies have shown that coupling of IgG to FcRI and IgE to FcRI induces conformational alterations in the ligands (40) and possibly in FcRI during an affinity shift(41) . Physical distances between FcR in aggregates (42) and interactions with cytoskeletal proteins may also be important(43) . Whether ligation changes the configuration of FcRI and how binding is communicated to cytoplasmic components will require further study.

In summary, the results in this report provide evidence that FcRI is altered by IgG-Fc interaction with the FcRI ligand-binding site and that this alteration permits efficient signaling of the oxidative inflammatory response. Phosphorylation of associated -chains and association by pp72Syk kinase were also increased by ligation of the receptors.

FOOTNOTES

*

This work was supported by Grant AI29455 from the National Institutes of Health (to L. C. P.) and by a grant from the Hitchcock Foundation, Hanover, NH. Flow cytometry was supported in part by the Core Grant of the Norris Cotton Cancer Center (CA23108). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed.

()

The abbreviations used are: FcR, Fc receptors; FcRI, high affinity Type I Fc receptor; FcRI, high affinity Fc receptor; IgG, immunoglobulin G; O, superoxide; IFN-, interferon ; FACS, fluorescence-activated cell sorting; PBS, phosphate-buffered saline; BSA, bovine serum albumin; FITC, fluorescein isothiocyanate.

()

L. C. Pfefferkorn and S. L. Swink, manuscript in preparation.

ACKNOWLEDGEMENTS

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