Immunization with IgG/Ag or IgE/Ag complexes leads to a higher production of specific Abs than immunization with Ag alone. The enhancing effect of IgE is exclusively dependent upon the low-affinity receptor for IgE, FcεRII, whereas the mechanism behind IgG-mediated enhancement is unknown. We have investigated whether receptors for the Fc part of IgG are required for responses to IgG/Ag. Mice lacking the γ subunit of Fc receptors (FcRs) (FcRγ−/−), FcγRII (FcγRII−/−), or FcγRIII (FcγRIII−/−) were immunized with BSA-2,4,6-trinitrophenyl (TNP) alone or BSA-TNP complexed to monoclonal TNP-specific IgG1, IgG2a, or IgG2b. As expected, all subclasses enhanced the Ab-response to BSA in wild-type mice. Enhancement was in the same order of magnitude in FcγRIII−/− mice (≤177-fold of controls administered Ag alone), whereas it was abrogated in FcRγ−/− mice and augmented in FcγRII−/− mice (≤5147-fold of controls). The response to IgE/Ag complexes in FcRγ−/− and FcγRII−/− mice was similar to that seen for wild-type mice, demonstrating that non-FcγR-dependent responses were normal. Our observations suggest that IgG/Ag complexes enhance Ab responses via FcγRs. Moreover, they reveal a strong negative regulation of Ab responses to IgG/Ag exerted by FcγRII.

In vivo, the Ab response after immunization with IgG/Ag complexes is often completely different from the response to Ag alone (reviewed in Ref. 1). The most well known effect of IgG is the suppression of responses to erythrocytes (2), which are used in the clinic to inhibit rhesus (Rh)3 immunization of Rh-negative women to their Rh-positive fetuses. IgG-mediated suppression of primary Ab responses seems to be independent of FcγRs and is most likely due to masking of epitopes by IgG Abs (3). Whether suppression of immunological memory is also Fc-independent or caused by negative signaling to the B cell via IgG/Ag-induced co-cross-linking of surface Ig and the inhibitory FcγRIIB remains to be investigated. In contrast, complexes of IgG and soluble protein Ags initiate much stronger in vivo Ab responses than Ag alone (4, 5, 6, 7, 8), and the same monoclonal 2,4,6-trinitrophenyl (TNP)-specific IgG can inhibit responses to SRBC-TNP while enhancing responses to keyhole limpet hemocyanin (KLH)-TNP (5, 7). In addition to IgG, IgE Abs are also able to up-regulate Ab responses to soluble Ags. An absolute requirement for IgE-mediated enhancement is a functional low-affinity receptor for IgE, FcεRII (CD23) (9, 10, 11). In vitro, IgE/Ag complexes are endocytosed by CD23+ B cells, followed by efficient presentation of Ag to T cells (12), and it is assumed that enhanced Ag presentation explains the IgE-mediated up-regulation of in vivo Ab responses. The mechanism behind IgG-mediated enhancement is less well understood. IgG complexes fulfill their biological functions via activating C or binding to FcγRs. Involvement of the C system was implicated in early studies, suggesting that IgG induced efficient responses by increasing the localization of Ag in lymphoid follicles (13). However, a non-C-activating mutant IgG was found to be almost as efficient in enhancing the immune response as the corresponding wild-type (wt) IgG (8). This finding suggests another mechanism, possibly involving FcγRs. There are three classes of FcγRs on murine leukocytes: FcγRI (CD64), FcγRII (CD32), and FcγRIII (CD16) (reviewed in Ref. 14). FcγRII and FcγRIII are low-affinity receptors for IgG1, IgG2a, and IgG2b. FcγRI is a high-affinity receptor for monomeric IgG2a and was recently reported to bind IgG3 also, although with moderate affinity (15). In the present study, a panel of FcγR-deficient mice were immunized with IgG/Ag or IgE/Ag (as a non FcγR-dependent control), and the role of these receptors in IgG-mediated enhancement of Ab responses was investigated.

The animals used herein were derived from FcγRIII−/− (16), FcRγ−/− (17), and FcγRII−/− mice (18), all of the H-2Ab haplotype. Because H-2b mice have an I-Ab-linked low responsiveness to IgE/BSA-TNP (19, 20) and IgG/BSA-TNP (19), the mutant mice were backcrossed to responder strains. FcγRIII−/− mice were crossed with CBA/J mice (H-2Ak)(Charles River, Someren, The Netherlands) or BALB/c mice (H-2Ad) (Charles River). FcRγ−/− and FcγRII/ mice were crossed with CBA/J mice (H-2Ak) (Bommice, Bomholtgaard, Ry, Denmark). The F1 generations were intercrossed, and homozygous mutant H-2Ad and H-2Ak mice as well as homozygous wt H-2Ak animals were identified by PCR analysis of tail DNA. Offspring from these animals were used in the experiments. Although the optimal strains would have been fully congenic mice, the most important gene locus for the studied Ab responses (I-A) was similar in mutant and wt animals. All mice were bred and maintained at the Department of Genetics and Pathology and the Department of Animal Development and Genetics (Uppsala University) or at the Department of Immunology (University Hospital Utrecht).

BSA, OVA, and TNP (picrylsulfonic acid/hydrate) were obtained from Sigma (St. Louis, MO). TNP was conjugated to BSA as described previously (20). BSA-TNP and OVA were stored in PBS at 4°C as sterile solution.

mAbs were derived from B cell hybridomas producing IgG1 anti-TNP (B8401H5(H5)), IgG2a anti-TNP (C4007B4(7B4)), IgG2b anti-TNP (C1901B4(1B4) GKH-1-GORK(GORK)), and IgE anti-TNP (IGELb4) and H5, 7B4, and 1B4 (6) as well as IGELb4 (21) have been described previously. GORK was a gift of Dr. G. Köhler (Max Planck Institute, Freiburg, Germany). IgG was purified on protein A- or protein G-Sepharose columns (Pharmacia, Uppsala, Sweden), and IgE was purified on a Sepharose column coupled with monoclonal rat anti-mouse κ. Abs were dialyzed against PBS, sterile-filtered, and stored at −20°C. Protein concentrations were determined by absorbance at 280 nm, assuming that an absorbance of 1.5 equals 1 mg/ml of Ab. The IgG subclass of the preparations was tested by ELISA using subclass-specific antisera (data not shown).

Mice were immunized in the tail vein with 0.1 ml of a PBS solution containing BSA-TNP or BSA-TNP/Ab complexes formed by incubating BSA-TNP with TNP-specific Abs for 1 h at 37°C immediately before injection. OVA were included in the Ag mixtures as a specificity control.

Blood was collected from the tail veins, and sera were tested using an IgG anti-BSA or IgG anti-OVA-specific ELISA (11). Statistical differences were determined by Student’s t test. p values are presented as: not significant, p > 0.05); ∗, p < 0.05; ∗∗, p < 0.01, or ∗∗∗, p < 0.001. Stimulation indices (SI) were calculated as the geometrical mean of the experimental group divided by the geometrical mean of the control group.

The γ subunit of Fc receptors (FcRγ) is associated with FcγRI, FcγRIII, FcεRI, and the TCR-CD3 complex. It is important for receptor assembly and mediates activating signals via an immunoreceptor tyrosine-based activation motif (ITAM) (reviewed in Ref. 14). Recently, the role of this receptor subunit has been studied in mice lacking FcRγ (17). These animals do not express FcγRIII or FcεRI, and their macrophages are unable to phagocytose IgG2a/SRBC complexes, which also suggests a lack of function of FcγRI. FcRγ−/− mice have defects in Ab-dependent cytotoxicity, hypersensitivity reactions, and phagocytosis (17, 22, 23), whereas the Ab response after immunization with KLH-4-hydroxy-3-nitrophenylacetyl in adjuvants is normal (24).

To study the role of FcγRs in IgG-mediated feedback enhancement, FcRγ−/− and wt mice were immunized with BSA-TNP alone or in complex with TNP-specific IgG1, IgG2a, or IgG2b (Fig. 1, A–C and E–G). As expected, all IgG isotypes enhanced the Ab response in wt mice. In FcRγ−/− mice, enhancement by IgG1 and IgG2a was almost completely inhibited; enhancement by IgG2b was reduced at early timepoints. The specificity of Ab feedback enhancement was tested by including the non-cross-reacting Ag OVA in all immunizations. IgG anti-OVA responses above background levels were not detected in any of the experiments described, and Abs injected alone were also unable to induce a response (data not shown).

FIGURE 1.

Impaired IgG-mediated enhancement of Ab responses in FcRγ−/− mice. Groups of four to five wt mice (A–D) and FcRγ−/− mice (E–H) were immunized i.v. with 20 μg of BSA-TNP (□) and 20 μg of OVA alone or in combination with 50 μg of TNP-specific IgG1 (A and E), IgG2a (B and F), IgG2b (C and G), or IgE (D and H) (▪). Sera taken from the mice at 14, 21, and 28 days postimmunization were tested for BSA-specific IgG by ELISA; the geometrical means in micrograms per milliliter are shown. The level of BSA-specific IgG in normal mouse serum (CBA/J) was 0.13 μg/ml. This experiment was repeated by injecting FcRγ−/− and wt mice with different amounts of IgG1, IgG2a (50, 10, and 2 μg), or IgG2b (250, 50, and 10 μg), giving similar results with 50 or 250 μg of Ab and no or low enhancement with lower doses (data not shown).

FIGURE 1.

Impaired IgG-mediated enhancement of Ab responses in FcRγ−/− mice. Groups of four to five wt mice (A–D) and FcRγ−/− mice (E–H) were immunized i.v. with 20 μg of BSA-TNP (□) and 20 μg of OVA alone or in combination with 50 μg of TNP-specific IgG1 (A and E), IgG2a (B and F), IgG2b (C and G), or IgE (D and H) (▪). Sera taken from the mice at 14, 21, and 28 days postimmunization were tested for BSA-specific IgG by ELISA; the geometrical means in micrograms per milliliter are shown. The level of BSA-specific IgG in normal mouse serum (CBA/J) was 0.13 μg/ml. This experiment was repeated by injecting FcRγ−/− and wt mice with different amounts of IgG1, IgG2a (50, 10, and 2 μg), or IgG2b (250, 50, and 10 μg), giving similar results with 50 or 250 μg of Ab and no or low enhancement with lower doses (data not shown).

Close modal

Because FcRγ is also associated with the TCR-CD3 complex, we wanted to exclude the possibility that the lack of Ab response was due to a defect in T cell help leading to a general inability to produce Abs after challenge with immune complexes. Therefore, mice were immunized with IgE anti-TNP and BSA-TNP. Although IgE was reported to bind to FcγRII and FcγRIII (25) as well as FcεRI, these receptors are unable to mediate responses to IgE/Ag complexes, as the ability of IgE to up-regulate Ab responses is completely inhibited in mice in which FcεRII is blocked by mAbs (9, 11) and in FcεRII−/− mice (10). Therefore, the unperturbed capacity of FcRγ−/− mice to respond to IgE/Ag complexes (Fig. 1, D and H) suggests that impaired Ab responses in these animals are seen primarily after immunization with IgG/Ag complexes. These data provide the first direct evidence that the ability of IgG1 and IgG2a to enhance in vivo Ab responses requires functional FcγRs.

Previous studies of mice selectively lacking FcγRIII demonstrated an important role of this receptor in inflammatory and anaphylactic responses and suggested that IgG1 complexes carry out their effector functions predominantly via FcγRIII (16, 26). To our knowledge, no reports regarding the Ab response in these mice have been published. FcγRIII−/− mice were immunized with BSA-TNP complexed to TNP-specific IgG1, IgG2b, or IgG2a. As shown in Table I (expts. 1 and 2), all isotypes were able to efficiently up-regulate the Ab response. When the Ab levels (ng/ml) were compared, the response in FcγRIII−/− animals immunized with IgG2b/Ag (expt. 1) or IgG2a/Ag (expt. 2) was not markedly different from the response in wt animals; the response to IgG1/Ag (expt. 1) was lower in FcγRIII−/− mice compared with wt mice. The differences in SI between the strains in expt. 1 can be explained by the fact that wt animals had a higher response to BSA-TNP alone than did FcγRIII−/− mice. We conclude from these experiments that mice lacking FcγRIII respond well to IgG/Ag complexes, and that the magnitude of the response is approximately the same as that seen in wt animals. To elucidate whether minor differences exist, more extensive studies need to be performed.

Table I.

IgG-mediated enhancement in FcγRIII−/− and FcγRII−/− micea

Expt.MicebImmunizationIgG Anti-BSA
Log10 ng/ml ± SDGeometrical meanpcSI
FcγRIII−/− BSA-TNP 2.24 ± 0.18 175  
  BSA-TNP+ IgG1 anti-TNP 4.49 ± 0.29 31,032 0.001 177 
  BSA-TNP+ IgG2b anti-TNP 4.42 ± 0.67 26,546 0.001 151 
 BALB/c BSA-TNP 3.54 ± 0.54 3,502  
  BSA-TNP+ IgG1 anti-TNP 5.22 ± 0.18 165,319 0.001 47 
  BSA-TNP+ IgG2b anti-TNP 4.68 ± 0.24 47,898 0.005 14 
FcγRIII−/− BSA-TNP 2.45 ± 0.18 281  
  BSA-TNP+ IgG2a anti-TNP 4.65 ± 0.27 45,005 0.001 160 
 FcγRIII+/+ BSA-TNP 2.49 ± 0.33 310  
  BSA-TNP+ IgG2a anti-TNP 4.52 ± 0.39 32,729 0.001 106 
FcγRII−/− BSA-TNP 2.29 ± 0.63 193  
  BSA-TNP+ IgG1 anti-TNP 6.00 ± 0.34 993,394 0.001 5,147 
  BSA-TNP+ IgG2a anti-TNP 4.71 ± 0.64 51,664 0.001 268 
  BSA-TNP+ IgG2b anti-TNP 5.76 ± 0.32 580,625 0.001 3,008 
  BSA-TNP+ IgE anti-TNP 4.99 ± 0.36 96,904 0.001 502 
 FcγRII+/+ BSA-TNP 2.02 ± 0.32 105  
  BSA-TNP+ IgG1 anti-TNP 4.44 ± 0.37 27,555 0.001 262 
  BSA-TNP+ IgG2a anti-TNP 3.03 ± 0.45 1,081 0.005 10 
  BSA-TNP+ IgG2b anti-TNP 3.49 ± 0.35 3,076 0.001 29 
  BSA-TNP+ IgE anti-TNP 4.60 ± 0.30 40,117 0.001 382 
Expt.MicebImmunizationIgG Anti-BSA
Log10 ng/ml ± SDGeometrical meanpcSI
FcγRIII−/− BSA-TNP 2.24 ± 0.18 175  
  BSA-TNP+ IgG1 anti-TNP 4.49 ± 0.29 31,032 0.001 177 
  BSA-TNP+ IgG2b anti-TNP 4.42 ± 0.67 26,546 0.001 151 
 BALB/c BSA-TNP 3.54 ± 0.54 3,502  
  BSA-TNP+ IgG1 anti-TNP 5.22 ± 0.18 165,319 0.001 47 
  BSA-TNP+ IgG2b anti-TNP 4.68 ± 0.24 47,898 0.005 14 
FcγRIII−/− BSA-TNP 2.45 ± 0.18 281  
  BSA-TNP+ IgG2a anti-TNP 4.65 ± 0.27 45,005 0.001 160 
 FcγRIII+/+ BSA-TNP 2.49 ± 0.33 310  
  BSA-TNP+ IgG2a anti-TNP 4.52 ± 0.39 32,729 0.001 106 
FcγRII−/− BSA-TNP 2.29 ± 0.63 193  
  BSA-TNP+ IgG1 anti-TNP 6.00 ± 0.34 993,394 0.001 5,147 
  BSA-TNP+ IgG2a anti-TNP 4.71 ± 0.64 51,664 0.001 268 
  BSA-TNP+ IgG2b anti-TNP 5.76 ± 0.32 580,625 0.001 3,008 
  BSA-TNP+ IgE anti-TNP 4.99 ± 0.36 96,904 0.001 502 
 FcγRII+/+ BSA-TNP 2.02 ± 0.32 105  
  BSA-TNP+ IgG1 anti-TNP 4.44 ± 0.37 27,555 0.001 262 
  BSA-TNP+ IgG2a anti-TNP 3.03 ± 0.45 1,081 0.005 10 
  BSA-TNP+ IgG2b anti-TNP 3.49 ± 0.35 3,076 0.001 29 
  BSA-TNP+ IgE anti-TNP 4.60 ± 0.30 40,117 0.001 382 
a

Groups of four to five mice were immunized i.v. with 20 μg of BSA-TNP and 20 μg of OVA alone or in combination with 25 μg (expt. 1) or 50 μg (expts. 2 and 3) of TNP-specific IgG1, IgG2a, IgG2b, or IgE. The BSA-specific IgG response in serum at 21 days postimmunization is shown. Sera analyzed at other timepoints gave similar results (data not shown). The level of BSA-specific IgG in normal mouse serum was 387 ng/ml (expt. 1, BALB/c), 206 ng/ml (expt. 2, FcγRIII−/−), 284 ng/ml (expt. 2, FcγRIII+/+), and 99 ng/ml (expt. 3, CBA/J). Experiment 3 was repeated by injecting FcγRII−/− and wt mice with 50, 10, or 2 μg of IgG1 or IgG2a, giving similar results with 50 μg of Ab and no or low enhancement in both strains with lower doses (data not shown).

b

FcγRII- or FcγRIII-deficient mice were backcrossed one generation to CBA/J mice (H-2Ak) (expts. 2 and 3) or to BALB/c mice (H-2Ad) (expt. 1). Their respective normal littermates (expts. 2 and 3) or BALB/c mice (expt. 1) were used as wt controls.

c

p value vs control value (c).

FcγRII contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) that inhibits activating signals in vitro through receptors containing ITAMs, such as the B cell Ag receptor (BCR), TCR, FcεRI, and human FcγRIIA (reviewed in Ref. 27). FcγRII also inhibits BCR-mediated endocytosis (28) and FcγRIIA-mediated phagocytosis (29). FcγRII is present in several isoforms, differing only in their cytoplasmic tails. The FcγRIIB2 isoform, which is expressed primarily on macrophages, is capable of endocytosing IgG/Ag complexes (30), whereas FcγRIIB1 is expressed on B cells and contains a sequence that inhibits endocytosis (30, 31). Both isoforms contain ITIM motifs and are capable of inhibiting cell activation (31). FcγRII−/− mice were shown to produce ∼5-fold higher Ab titers than wt mice after immunization with KLH-TNP (in adjuvant) or SRBC (18). To study the role of FcγRII in IgG-mediated enhancement of Ab responses to soluble protein Ags, FcγRII−/− and wt mice were immunized with BSA-TNP alone or complexed with IgG or IgE anti-TNP. As expected, the response to IgG/Ag or IgE/Ag in wt mice was significantly higher than the response to Ag alone (Table I, expt. 3). In FcγRII−/− mice, IgG/Ag complexes were not only able to enhance Ab responses, but did so much more efficiently (36- to 189-fold, calculated from the nanogram per milliliter levels of IgG) than in wt animals. In contrast, the response to IgE/Ag was only marginally higher (2.4-fold) in FcγRII−/− mice compared with wt mice.

The titer of circulating Ab is the net result of Ab production and Ab catabolism. Throughout this manuscript, we have used the term Ab response, assuming that the differences in Ab titers reflect differences in Ab production rather than Ab catabolism or protection from catabolism. We find this to be a reasonable assumption, because the only FcR known to play a role in IgG catabolism is the neonatal FcR, FcRn (32), which is not studied here. In this work, we have observed an almost complete lack of response to IgG1/Ag and IgG2a/Ag in FcRγ−/− mice. The fact that FcRγ−/− mice do not express functional FcγRI or FcγRIII (17) suggests that the binding of IgG/Ag to one or both of these receptors is of primary importance for the ability of IgG to up-regulate primary Ab responses to soluble Ag. Assuming that the FcγRII in FcRγ−/− mice operates normally, the low response to IgG/Ag in this strain leads to the conclusion that FcγRII is not capable of inducing significant IgG-mediated enhancement; this interpretation is supported by the strong responses to IgG/Ag in FcγRII−/− mice. The fact that FcγRIII−/− mice respond well to IgG/Ag leads to the conclusion that FcγRI is sufficient for the response to IgG/Ag. It could be the only receptor involved, although it cannot be excluded that FcγRIII acts in concert with FcγRI. Involvement of FcγRI is not surprising, given that targeting of Ag to human FcγRI leads to increased Ag presentation in vitro (33, 34) and to higher Ab production in mice transgenic for human FcγRI (35). Although FcγRI only binds IgG2a with high affinity, it is possible that other IgG isotypes in complex with Ag are also captured. Interestingly, when the third extracellular domain of FcγRI is removed, the receptor gains the capacity to bind IgG1 and IgG2b (36), and a unique allele of FcγRI in nonobese diabetic mice binds IgG2b with high affinity (37). There is a small residual enhancement in FcRγ−/− mice. This may be due to a minor contribution of the C system and agrees with previous findings that non-C-activating IgG was able to enhance Ab responses, but that the C-activating wt IgG was slightly more effective (8). Because the FcRγ chain is not exclusive for FcγRs, but is also present in the TCR, the lack of Ab response after immunization with IgG/Ag could hypothetically be due to a lack of proper T cell help. However, we find this possibility unlikely, because the response to IgE/Ag complexes (which is independent of FcγRs, but presumably needs the same T cell help as responses to IgG/Ag) is at least as efficient in FcRγ−/− mice as in wt mice (Fig. 1, D and H). In vitro, IgG/Ag complexes are efficiently taken up via FcγR-mediated endocytosis by macrophages or dendritic cells and presented to Th cells (38, 39, 40). It is an attractive possibility that this mechanism, operating in vivo, results in an IgG-mediated enhancement of Ab responses. This means of inducing Ab responses could be of particular importance in the induction of secondary immune responses when specific IgG, generated during priming, is already present at the time of Ag encounter.

Our second major finding is the demonstration of a negative regulatory role of FcγRII in the response to IgG/Ag (Table I, expt. 3). The response to IgG/Ag in FcγRII−/− mice is much higher than in wt controls, and the FcγRII-mediated “suppression” seen in this system seems to be even more striking than the inhibitory effect on responses to SRBC or KLH-TNP administered in CFA (18). The most straightforward mechanism behind the inhibition of responses to IgG/Ag is that the complexes co-cross-link the BCR and FcγRII, thereby inhibiting optimal B cell signaling after recognition of Ag. Such negative regulation of B cell activation has been well documented in vitro (31, 41). An interesting possibility is that inhibition also takes place at an earlier step in the chain of events leading to Ab production. Co-cross-linking of FcγRII and the FcγR capturing and internalizing the IgG/Ag complexes (presumably FcγRI (and FcγRIII), both containing ITAMs) may inhibit efficient presentation to T cells.

We thank I. Brogren for excellent technical assistance, Dr. S. Applequist for critical review of the manuscript, Dr. J. V. Ravetch for the gift of FcRγ−/− and FcγRII−/− founder animals, Dr. M. Wabl for IgE, and Dr. P. Coulie for IgG hybridomas.

1

This work was supported by Agnes and Mac Rudberg’s Foundation; Lilly and Ragnar Åkerham’s Foundation; The Ellen, Walter, and Lennart Hesselman’s Foundation; Hans von Kantzow’s Foundation; King Gustaf V’s 80 Year Foundation; The Swedish Medical Research Council; and The Swedish Foundation for Health Care Sciences and Allergy Research.

3

Abbreviations used in this paper: Rh, rhesus; TNP, 2,4,6-trinitrophenyl; KLH, keyhole limpet hemocyanin; FcR, Fc receptor; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif;CR, B cell Ag receptor; SI, stimulation index; wt, wild type.

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