Allergen-directed expression of Fc receptors for IgE (CD23) on human T lymphocytes is modulated by interleukin 4 and interferon-gamma

T lymphocytes bearing Fc receptors (FcR) for immunoglobulins are known to have immunoglobulin class-specific regulatory functions. Here we report that expression on T cells of the low-affinity FcR for IgE (Fc epsilon RII/CD23) is preferentially induced by stimulation with antigens that cause an IgE response. T cells from eight patients allergic to the hemoglobin of Chironomus thummi thummi mosquito larvae (CHIT I) were analyzed for reactivity with the anti-FcERII/CD23 monoclonal antibody (mAb) M-L25 under various conditions. No Fc epsilon RII/CD23+ T cells were observed among freshly isolated, resting peripheral blood mononuclear cells (PBMC). Stimulation of PBMC with CHIT I, however, induced a marked although transient Fc epsilon RII/CD23 expression on a large portion of the allergen-activated T lymphocytes. It reached a maximum of 37.2 +/- 4.6% Fc epsilon RII/CD23+ T cell blasts on day 5 of culture. The selectivity of this expression became evident when compared to non-allergenic control antigens: after stimulation of PBMC with tetanus toxoid or purified protein derivative from tuberculin a maximum of 4.6% +/- 1.4% and 4.2% +/- 1.1% T cell blasts was found to express Fc epsilon RII/CD23, respectively. Activation by an anti-CD3 mAb was insufficient to induce Fc epsilon RII/CD23 on T cells. The allergen-stimulated Fc epsilon RII/CD23+ T cells exclusively belonged to the CD4+CD29+ helper inducer T cell subset. Using a cDNA probe coding for the B cell Fc epsilon RII/CD23, Northern blot analysis revealed a 1.7-kb Fc epsilon RII/CD23 mRNA in extracts of highly purified allergen-stimulated T cells. It was of the same size as Fc epsilon RII/CD23 mRNA of the lymphoblastoid B cell line WI-L2. Of several cytokines tested [interleukin (IL) 1 to IL 6, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha] only IL 4 and IFN-gamma significantly modified allergen-induced Fc epsilon RII/CD23 expression on T cells. The latter was enhanced nearly twofold in the presence of IL 4, and was almost completely abrogated by IFN-gamma. IL 4, however, could not increase the number of Fc epsilon RII/CD23+ T lymphocytes either alone or in combination with an anti-CD3 mAb. Taken together, the selective induction of Fc epsilon RII/CD23 on T cells by allergen and its inclusion in the regulatory network of cytokines point to an important role of Fc epsilon RII/CD23+ T lymphocytes in the human IgE response.     

Affinity-purified soluble Fc epsilon RII/CD23 derived from RPMI-8866 cells induces histamine release from human nasal polyp mast cells through a non-IgE-mediated mechanism.

Soluble Fc epsilon RII/CD23 (IgE-binding factor) is released spontaneously from activated B cells and most EBV-immortalised B cell lines. We have purified soluble Fc epsilon RII/CD23 from culture supernatants of RPMI-8866 cells on an IgE Sepharose column, and studied its ability to release histamine from human nasal polyp mast cells. Soluble Fc epsilon RII/CD23 induces release of a significant amount of histamine from nasal polyp mast cells in a dose-dependent manner. IgE, and a monoclonal antibody specific for the soluble form of this receptor, were shown to neutralise this effect. It was found that soluble Fc epsilon RII/CD23 was still capable of triggering histamine release from nasal polyp mast cells from which IgE had been eluted by incubation in a low pH buffer, suggesting that a non-IgE mediated mechanism was responsible for this effect.     

Expression,regulation and function of human FcεRII (CD23) antigen

CD23, also known as the low affinity receptor for IgE (Fc epsilon RII), belongs to a novel superfamily of type-II integral membrane proteins. Fc epsilon RII expression was originally described on B cells but subsequent studies showed that CD23 is expressed on a variety of hematopoietic cells and is regulated by several cytokines (i.e., interleukin-4, interferons) in a tissue-specific manner. In some pathological conditions such as B-chronic lymphocytic leukemia, the CD23 gene is abnormally regulated resulting in CD23 overexpression. CD23 is not only an IgE receptor but also a membrane-bound precursor of soluble molecules that still bind IgE (sCD23 or IgE-binding factors). The functions of membrane CD23 are IgE-dependent and vary according to the cell types on which it is expressed. In contrast, sCD23, in addition to being an IgE regulatory molecule, displays multiple cytokine activities that are IgE-independent.     

Induction and function of Fc epsilon RII on YT cells; possible role of ADF/thioredoxin in Fc epsilon RII expression.

The regulation of low-affinity Fc receptor for IgE (Fc epsilon RII) and the characteristics of both membrane and soluble forms of Fc epsilon RII were studied using YT cell line. We found that YT cells, a human NK like cell line, expressed Fc epsilon RII after IL-1 stimulation. Cross-linking of Fc epsilon RII on IL-1-stimulated YT cells as well as the transfectant of Fc epsilon RII-cDNA (YTSER) resulted in the up-regulation of IL-2R alpha (p55/Tac). A 59 kDa protein phosphorylated at tyrosine residues was co-immunoprecipitated with Fc epsilon RII from YTSER lysate using H107 anti-Fc epsilon RII mAb. YTSER not only expressed Fc epsilon RII on their surface but also secreted soluble form of Fc epsilon RII (sFc epsilon RII/sCD23; IgE binding factor). Affinity purification revealed that sFc epsilon RII released from YTSER is heterogeneous and consisted of several proteins differing in molecular weight. Both EBV+ B cells and HTLV-1+ T cells are high producers of ATL derived factor (ADF)/thioredoxin (TRX) and express Fc epsilon RII and IL-2R alpha respectively. To clarify the mechanism of Fc epsilon RII and IL-2R alpha induction by ADF/TRX, we examined the effect of ADF/TRX on the bindability of nuclear factor kappa B (NF-kappa B), which is known to regulate IL-2R alpha gene expression. In the gel shift assay, ADF/TRX was shown to enhance the bindability of NF-kappa B to its responsive element.     

IgE: an immunoglobulin specialized in antigen capture?

IgE bound to the low-affinity receptor for immunoglobulin E (Fc epsilon R) on antigen-presenting cells (APCs) may permit binding of antigens to APCs prior to their processing and presentation. Here, G. C. Mudde and colleagues argue that the unique characteristics of IgE serological responses together with the distribution of Fc epsilon RII (CD23) on APCs are consistent with this novel function of IgE. The concept of IgE involvement in antigen capture is discussed in relation to Langerhans cells, B cells and follicular dendritic cells.     

IgE-dependent antigen focusing by human B lymphocytes is mediated by the low-affinity receptor for IgE

In this study we investigated the role of the low-affinity receptor for IgE (Fc epsilon RII, CD23) on Epstein-Barr virus (EBV)-transformed human B cells in the uptake and presentation to T cells of antigen after complexing with IgE. Cloned EBV-transformed B cells were incubated for 5 h with (4-hydroxy-3-iodo-5-nitrophenyl)acetyl (NIP)-haptenized tetanus toxoid (NIP-TT) or NIP-TT complexed with a chimeric human IgE/mouse anti-NIP monoclonal antibody (IgE x NIP-TT) and then contacted for 2 min with autologous cloned TT-specific T cells. Intracellular Ca2+ mobilization in T cells was determined as an early indicator of T cell activation. The antigen-presenting capacity of B cells was significantly increased by complexing the antigen with IgE. This effect could be selectively reversed in a dose-dependent manner by blocking the Fc epsilon RII with an anti-CD23 monoclonal antibody. The IgE-mediated increased capacity for presenting antigen became particularly evident when B cells were incubated with NIP-TT or IgE x NIP-TT for only 1 h at 4 degrees C, washed and then cultivated for 6 h at 37 degrees C allowing uptake and processing of the antigen. These results indicate a new role of the Fc epsilon RII/CD23 molecules in the uptake of antigen by APC which might be of importance in the maintenance of an ongoing immune response against allergens.     

Studies on the role of interleukin-4 and Fc epsilon RII in the pathogenesis of minimal change nephrotic syndrome.

Childhood minimal change nephrotic syndrome (MCNS) has often been associated with allergic symptoms such as urticaria, bronchial asthma, atopic dermatitis, allergic rhinitis and elevated IgE levels and referred to involve immune dysfunction. Fc epsilon RII is known to be involved in IgE production and response. Interleukin-4 is being recognized as a major cytokine up-regulating IgE production. Hence the present study is aimed at investigating the role of interleukin-4 and Fc epsilon RII in the pathogenesis of MCNS. IgE was measured by ELISA. Fc epsilon RII was analyzed by fluorescence activated cell scanner (FAC-scan) by double antibody staining with anti Leu16-FITC and anti Leu20-PE. Soluble IgE receptor was measured by ELISA using anti CD23 antibody (3-5-14). Interleukin-4 activities were measured by CD23 expression on purified human tonsillar B cells. Serum IgE levels were significantly higher in MCNS (1,507 +/- 680 IU/dl) than in normal controls (123 +/- 99.2 IU/dl). A significantly higher expression of membrane Fc epsilon RII was noted for MCNS (41 +/- 12%) than that in normal controls (18 +/- 6.2%) (p < 0.001). Soluble CD23 levels were also significantly higher in MCNS (198 +/- 39.3%) than in normal controls (153 +/- 13.4) (p < 0.01). Interleukin-4 activity in sera of MCNS (12U/ml) was also significantly higher than normal controls (4.5U/ml). These results indicate that increased production of Fc epsilon RII and interleukin-4 may play an important role in the pathogenesis of MCNS.     

Induction of Fc epsilon RII/CD23 on PHA-activated human peripheral blood T lymphocytes and association of fyn tyrosine kinase with Fc epsilon RII/CD23.

Despite the evidence for the expression of Fc epsilon RII/CD23, a glycoprotein that is a low-affinity Fc receptor for IgE, obtained on T cell lines and some pathological T cells, that of Fc epsilon RII/CD23 on normal human T cells is still unclear. We studied the emergence of T cells bearing Fc epsilon RII/CD23 in short-term culture of normal human peripheral blood mononuclear cells stimulated with 15 microliters/ml phytohemagglutinin (PHA). Using two-dimension flow cytometry, more than 10% of Fc epsilon RII/CD23(+) cells were shown to co-express CD3 antigen. Both CD4(+) and CD8(+) T cells expressed Fc epsilon RII/CD23. The expression of mRNA for Fc epsilon RII/CD23 on PHA and IL-4 stimulated PBMC was demonstrated by northern blotting and in-situ hybridization. The mechanism of signal transduction through Fc epsilon RII/CD23 was dissected by transfection of cDNA coding for Fc epsilon RII to the human natural killer-like cell line YT, activation of which was easily detected by the induction of interleukin-2 receptor/p55 (Tac). Cross-linking of Fc epsilon RII/CD23 with H107 anti-Fc epsilon RII monoclonal antibody enhanced IL-2R/p55 expression on YT cells transfected with Fc epsilon RII cDNA (YTSER). A possible involvement of protein-tyrosine kinase in the Fc epsilon RII-mediated signal transduction was studied using YTSER. Fc epsilon RII was physically associated with an src-family tyrosine kinase p59fyn and not with p56lck, which was also found in YT cells. Recently it was reported that p59fyn was associated with T-cell antigen receptor. Our results collectively suggest the multiple function of p59fyn which may be implicated in the Fc epsilon RII-mediated activation signal in YT cells.     

CD23: a multi-functional receptor/lymphokine?

With the demonstration of identity between CD23 and the low affinity IgE Fc receptor (Fc epsilon RII), two previously separate avenues of immunological research have converged into one. Particularly in its guise as 'Blast-2' antigen, evidence has been mounting to implicate CD23 as an important molecule in B-cell growth regulation. It might seem pertinent, however, to question a role for an apparently isotype-specific immunoglobulin (Ig) receptor in general B-cell processes. In this article, John Gordon and colleagues attempt to reconcile the two, currently diverse, schools of thought regarding the primary function of CD23 and to provide a structural model that accounts for the biological pleiotropy observed.     

Spontaneous and ligand-induced endocytosis of CD23 (Fc epsilon receptor II) from the surface of B lymphocytes generates a 16-kDa intracellular fragment.

It has been reported that the 45-kDa low-affinity Fc epsilon receptor (Fc epsilon RII) on B cells is cleaved spontaneously from the cell surface to release soluble fragments. This study demonstrates an additional fate of the Fc epsilon RII. 125I-labeled CD23+ B cells were cultured for 24 h at 37 degrees C. After lysis, cell extracts were immunoprecipitated with CD23 monoclonal antibodies. Using this methodology, we demonstrated that an increasing amount of the labeled Fc epsilon RII becomes progressively resistant to externally applied trypsin, indicating that a fraction of the cell surface receptors are internalized. In parallel, a labeled 16-kDa material, recognized by CD23 monoclonal antibodies directed to the lectin-like domain of the Fc epsilon-RII appears inside the cells. Chloroquine does not affect internalization of the Fc epsilon RII, but completely abolishes the formation of the intracellular fragment, suggesting that the receptor is processed by proteolytic cleavage in acidic organelle. In addition, the internalization is enhanced in the presence of CD23 monoclonal antibodies. These data demonstrate that Fc epsilon RII can be internalized by ligand-induced endocytosis and subsequently cleaved in an intracellular compartment. These results also support the view that the Fc epsilon RII is involved in antigen focusing and antigen presentation.     

Eosinophil IgE receptor and CD23

In the present review, eosinophil Fc epsilon RII was compared to CD23, a differentiation marker of B cells. Biochemical analysis revealed that molecules of similar molecular weight were immunoprecipitated from eosinophils and B cells by an anti-CD23 monoclonal antibody (mAb) or by BB10, and anti-eosinophil Fc epsilon RII. By flow cytometry, a correlation was found between the binding of anti-CD23 mAb and myeloma IgE. However, a low expression of different epitopes of CD23 was observed in various hypereosinophilic patients. Northern blot analysis of eosinophil RNA with the cDNA probe of CD23 revealed a weak message in only 3 of the 6 patients expressing membrane CD23. The inhibition by anti-CD23 mAbs of IgE-mediated cytotoxicity and IgE binding to eosinophils clearly indicated the participation of CD23 or a related molecule in IgE-dependent eosinophil functions. However, the differential effects of anti-CD23 mAbs on eosinophils and B cells suggest major differences in the characteristics of the molecule expressed by eosinophils and by B cells.     

Decreased serum levels of IgE and IgE-binding factors in individuals infected with HTLV-I.

The cell surface expression of low-affinity Fc epsilon receptor (Fc epsilon RII), which is identical to CD23, and the serum levels of IgE binding factors (IgE BFs), a soluble form of Fc epsilon RII, and IgE were investigated in HTLV-I-infected individuals, and the results were compared with those for HTLV-I-negative controls. The occurrence of Fc epsilon RII+ mononuclear cells did not differ among the blood samples from the HTLV-I-infected groups; however, the levels of serum IgE BFs were significantly decreased (P less than 0.001) in patients with adult T cell leukaemia (ATL), compared with HTLV-I-negative controls. The serum IgE levels were also significantly decreased in these groups, including cases of ATL (P less than 0.001) and HTLV-I-associated myelopathy (P less than 0.05), and HTLV-I carriers (P less than 0.05), as compared with HTLV-I-negative controls. Since cases of strongyloidiasis or filariasis are frequently found among HTLV-I-infected individuals in Japan, these results may explain in part their defective defence mechanisms for parasites. The possible involvement of IgE BFs in the development of immune deficiency state in HTLV-I infection is also discussed.     

Fc epsilon receptor II/CD23-positive lymphocytes in atopic dermatitis. I. The proportion of Fc epsilon RII+ lymphocytes correlates with the extent of skin lesion.

Cells expressing Fc receptors for IgE (Fc epsilon RII) were identified in the peripheral blood from patients with atopic dermatitis and with eczematous dermatitis, and normal non-atopic subjects by using monoclonal antibodies to human lymphocyte Fc epsilon RII, and to lymphoid cell-surface antigens by immunofluorescence staining. Based on the extent of the dermatitis patients were classified as severe (greater than 50% skin surface involved), moderate (50-10%) and mild (less than 10%). Patients with severe and moderate atopic dermatitis had 5.9% and 5.7% Fc epsilon RII+ peripheral blood mononuclear cells (PBMC), respectively, that were significantly higher than percentages in mild atopic dermatitis patients (2.6%), severe to moderate eczematous dermatitis patients (2.3%), mild eczematous dermatitis patients (2.2%) and normal individuals (1.7%)(0.05 greater than P). In severe and moderate atopic dermatitis patients, 10% of Fc epsilon RII+ PBMC were T cells that preferentially expressed CD8, and the remainder B cells and monocytes. Fc epsilon RII+ T cells comprised 1% of peripheral T cells, while half or more of peripheral B cells expressed Fc epsilon RII. In mild atopic dermatitis patients, eczematous dermatitis patients and normal subjects. Fc epsilon RII were expressed exclusively on 25-35% of peripheral B cells. Short-term treatment and long-term follow-up of atopic dermatitis patients revealed that changes in the skin condition were related closely to fluctuations in the proportion of Fc epsilon RII+ PBMC. Total serum IgE levels and atopic respiratory allergy did not influence the percentage of Fc epsilon RII+ PBMC. These findings suggest that the percentage of Fc epsilon RII+ PBMC reflects the extent of atopic dermatitis.     

Regulation of the expression of the low-affinity IgE receptor (Fc epsilon RII) in the human monocyte-like cell line U-937 by phorbol esters and IgE

The expression of the low-affinity receptor for IgE Fc epsilon RII) in the human monocyte-like U-937 cell line can be upregulated by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) and by IgE. TPA induces terminal differentiation of U-937 cells and causes a four- to fivefold increase in the number of Fc epsilon RII. TPA also modulates the expression of several other membrane markers of U-937 cells. IgE alone has a modest effect on the expression of Fc epsilon RII (about a 10% increase), while simultaneous treatment of U-937 cells with TPA and IgE has a cooperative effect, causing an eightfold increase in the number of Fc epsilon RII. Cycloheximide strongly suppresses the expression of Fc epsilon RII, both in TPA-stimulated and unstimulated cells; this effect can be partly reversed by culturing the cells in the presence of IgE. These results suggest that TPA induces the expression of newly synthesized receptors, while IgE causes an accumulation of preformed receptors.     

Regulation by interleukin 2 of CD23 expression of leukemic and normal B cells: comparison with interleukin 4

Recombinant interleukin (IL) 4 has been shown to be able to up-regulate low-affinity Fc receptor for IgE (Fc epsilon RII)-CD23 expression on B cells as well as on other human mononuclear cells. We demonstrate here that, in opposition with previous reports, recombinant IL2 also can up-regulate CD23 expression on B cells. This was first observed on CLL cells which represent a monoclonal proliferation of B cells arrested at an intermediate stage of activation. Cells of 5 out of 12 B-CLL studied display such an increase and all 5 proliferated, in vitro, directly in response to IL2. Similarly, upon triggering with anti-mu and IL2, normal tonsillar B lymphocytes also demonstrate an increase of CD23 expression but this was observed only on day 3. Interferon-gamma was able to inhibit this IL2-mediated up-regulation of CD23 on normal B cells but not on CLL-B cells; on those cells interferon-gamma was similarly unable to inhibit the IL4-mediated CD23 up-regulation. These results suggest that CD23 regulation is complex and related to the stage of activation and the cell type.     

Tumour necrosis factor-alpha augments the expression of Fc IgE receptor (Fc epsilon RII/CD23) on human monocytic cell lines and down-regulates interleukin-4-driven Fc epsilon RII expression on monocytes.

We investigated the expression of the low affinity Fc IgE receptor (Fc epsilon RII/CD23) on the human monocytic cell lines U937, THP-1, Mono-Mac-6, and cultured human peripheral blood monocytes under stimulation with human tumour necrosis factor-alpha (TNF-alpha) and other cytokines. Fc epsilon RII was demonstrated by flow cytometry analysis employing the anti-Fc epsilon RII monoclonal antibody 3-5. TNF-alpha alone had a weak but significant stimulating effect on the Fc epsilon RII expression on the cell lines U937 and THP-1, and very modestly on Mono-Mac-6 cells. TNF-alpha strongly synergized with interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). IFN-alpha per se was ineffectual, but was able to increase the TNF-alpha effect. Furthermore, the action of TNF-alpha was slightly augmented by human IL-6. Similar effects were noted with TNF-beta alone or in combination with other cytokines. Interestingly, on human monocytes TNF-alpha weakly reduced the basal level of Fc epsilon RII, and markedly diminished the IL-4-induced Fc epsilon RII expression. Our results indicate that several cytokines may interact in a cytokine network to modulate Fc epsilon RII expression on monocytic cell lines. On human blood monocytes, TNF-alpha, like IFN-gamma or IL-6, counteracts the IL-4-induced Fc epsilon RII expression. These data suggest different regulatory pathways of Fc epsilon RII expression on blood monocytes and myelomonocytic cell lines.     

Influence of IL-2 and IL-4 on the IgE synthesis and the IgE-binding factor (sCD23) production by human lymphocytes in vitro.

The influence of IL-2 and IL-4 on the mitogen-induced immunoglobulin E and IgG production in vitro was analysed. Furthermore the expression of Fc epsilon RII (CD23 antigen), as well as the release of its soluble products, the isotype-specific IgE binding factors (IgE-BF), was determined. Recombinant IL-2 (rIL-2) exerted opposite effects on the synthesis of IgE by human lymphocytes that were stimulated either by pokeweed mitogen (PWM) or Staphylococcus aureus Cowan I (SAC). rIL-2 induced a dose-dependent suppression of IgE and IgG synthesis in the presence of PWM. This effect was accompanied by a significant decrease of IgE-binding factor (BF), whereas the expression of Fc epsilon RII was not significantly modulated by rIL-2. A marked increase of IgE production was observed when lymphocytes, prestimulated with SAC for 48 hr, were further incubated with increasing amounts of rIL-2 for 6 days. In contrast, IL-4 in concentrations ranging from 500 to 4.9 U/ml did not lead to an enhancement of IgE synthesis in lymphocytes that were prestimulated with SAC. However, SAC-induced IgG secretion was significantly enhanced by 2.3 U/ml of rIL-4. A dose-dependent enhancement of IgE-BF was observed in SAC-prestimulated lymphocyte cultures in the presence of rIL-2 as well as rIL-4. These results demonstrate that the mitogen used for lymphocyte activation, T-cell-derived lymphokines such as IL-2 and IL-4, and IgE-specific binding factors (soluble CD23), are responsible for the induction of human IgE antibody production in vitro.     

Effect of anti-IgE antibodies on IgE binding to CD23

Human sera contain anti-IgE autoantibodies. Using a human B lymphoblastoid cell line (Wil-2WT cells) and monoclonal murine anti-IgE antibodies (BSW17 and Le27) we investigated a possible role of such anti-IgE antibodies. A 100-fold excess of monoclonal anti-IgE antibodies inhibited binding of 125I labeled IgE to Fc epsilon RII on Wil-2WT cells. Further, both monoclonal anti-IgE antibodies dissociated surface bound IgE from Fc epsilon RII on Wil-2WT cells. However, BSW17 which does not trigger histamine release from human leucocytes, was much more effective in dissociating Fc epsilon RII bound IgE than Le27 which triggers histamine release. These results may suggest that naturally occurring IgG anti-IgE antibodies are able to inhibit binding of IgE to its receptor.     

Inhibition of interleukin 4-promoted CD23 production in human B lymphocytes by transforming growth factor-beta, interferons or anti-CD19 antibody is overriden on engaging CD40.

Interleukin 4 (IL 4) is an essential component in the sequence of events directing IgE synthesis in uncommitted B lymphocytes. An early consequence of IL 4's interaction with the B cell is the induction of CD23, a low-affinity receptor for IgE (Fc epsilon RII). The present study was designed to explore the detailed regulation of this event. First, we report that transforming growth factor-beta (TGF-beta) is a potent inhibitor of IL 4-promoted CD23 production in human B lymphocytes. The level of inhibition achieved with TGF-beta was greater than that obtained with interferons, or with a monoclonal antibody (mAb) to CD19. Next, we identified three signals, each of which was capable of selectively counteracting the inhibitors of IL 4-promoted CD23 production: (a) the engagement of surface CD40 antigen with mAb was found to override the influence of all the inhibitors of CD23 expression; (b) mAb to surface IgM overcame the inhibitory actions of TGF-beta and interferons but not that of CD19 ligation; (c) ligation of surface CD72 counteracted the inhibition mediated by TGF-beta but not that generated by interferons or anti-CD19 antibody. Inhibition of the IL 4 signal appeared to be selective for the pathway leading to CD23 induction: none of the inhibitors profoundly altered IL 4's ability to enhance surface IgM expression. The study has ramifications for the understanding of events leading to the promotion of IgE synthesis and consolidates the notion of a central role for CD40 in B cell regulation.