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(Journal of Leukocyte Biology. 2000;68:511-514.)
© 2000 by Society for Leukocyte Biology

Activation-dependent expression of the blood group-related Lewis Y antigen on peripheral blood granulocytes

M. Dettke*, G. Pálfi and H. Loibner

NOVARTIS Forschungsinstitut Vienna and
* AKH Vienna, Department for Blood Serology and Transfusion Medicine, University of Vienna, Vienna, Austria

Correspondence: Dr. Markus Dettke, AKH Vienna, Department for Blood Serology and Transfusion Medicine, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: markus.dettke{at}univie.ac.at


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ABSTRACT
 
The expression of the difucosyl-lactosamine type 2 oligosaccharide Lewis Y (LeY) on peripheral blood cells was investigated. As assessed by the reactivity with the mouse anti-LeY monoclonal antibody (mAb) ABL 364 among circulating blood cells, the expression of the LeY oligosaccharide was uniquely restricted to granulocytes. Although the density of LeY expressed on resting granulocytes was weak, in vitro activation of granulocytes with fMLP induced a rapid and pronounced increase in granulocyte LeY expression. Analysis of CEA-related glycoproteins immunoprecipitated with anti-CD66 mAbs followed by immunoblotting with mAb ABL 364 showed that granulocyte LeY is attached to members of the CD66 cluster, in particular to the 160/90 kD glycoprotein recognized by anti-CD66 mAb CBL/gran 10. The activation-associated increase in LeY attached to CD66 adhesion molecules implicates a role of the LeY determinant in the cytoadhesive properties of granulocytes.

Key Words: granulocytes • Lewis Y antigen • CD66 • nonspecific-crossreacting antigen


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INTRODUCTION
 
Neutrophil granulocytes play a central role in the defence against infection and the generation of inflammation. The primary neutrophil functions of chemotaxis, phagocytosis, and degranulation involve complex intercellular interactions that depend on the adhesive properties of the neutrophil plasma membrane. Several of these functions have been addressed to blood group-related oligosaccharides of the Lewis (Le) family. Based on the type I or type II lactosamine oligosaccharide precursor chain, the Le antigens and their sialylated and sulfated derivates have been implicated in the initial steps of cell recognition and adhesion [1 ]. In particular, sialyl-LeX (sLeX) and related carbohydrate structures function as cellular ligands recognized by various adhesion molecules, such as vascular E- and P-selectin [2 , 3 ].

Although the expression of LeX and sLeX on human granulocytes is well established, less is known about the expression of the difucosyl form of the type II precursor chain, LeY. Originally detected and characterized as an oligosaccharide expressed on mucins of an ovarian cyst adenoma [4 ], the LeY determinant has been identified as an oncofetal carbohydrate antigen related to ontogenesis [5 ], cellular apoptosis [6 , 7 ], and human cancer [8 , 9 ]. Less is known, however, about the physiological role of LeY.

There is evidence that LeY is involved in the process of cellular adhesion and cellular motility [10 ]. Monoclonal antibodies (mAbs) directed against LeY or a related parietal structure (i.e., Fuc{alpha}1->2Galß1->R, which is shared by H/LeY/LeB antigens) were shown to inhibit locomotion of LeY-bearing tumor cells in vitro [11 , 12 ]. Moreover, in the mouse model, LeY seemed to act as a mediator molecule essential for the initial stage of embryo implantation [13 , 14 ].

Despite its expression on various types of human cancer, recent data indicate that the LeY determinant is also expressed on cells of the hematopoietic system. Muroi et al. [15 ] demonstrated the expression of the LeY hapten on matured peripheral blood cells and various leucemic cell lines, as identified by the reactivity with the anti-LeY mAb AH-6. Using a panel of different anti-LeY mAbs, Kitamura et al. [16 ] confirmed the expression of the LeY oligosaccharide on circulating blood cells, even if in this study the expression of LeY was restricted to granulocytes. Under certain pathological circumstances, the LeY is also expressed on cells of lymphoid lineage, e.g., human immunodeficiency virus (HIV)-infected lymphocytes [17 ].

In the present study, we analyzed the expression and regulation of the LeY oligosaccharide on peripheral blood cells, as defined by the reactivity with the anti-LeY mAb ABL 364. Our data showed that in the human peripheral blood, granulocytes represent the only cells expressing LeY. Although LeY expression was weak on resting granulocytes, in vitro challenge with formyl-Met-Leu-Phe (fMLP) led to a rapid increase in granulocyte LeY expression, which seemed to be related to an increased expression of the CD66 antigens on the granulocyte membrane surface.


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MATERIALS AND METHODS
 
Monoclonal anti-LeY antibodies
The characterization and purification of the mIgG3 anti-LeY mAb ABL 364 and its respective F(ab)'2 fragment have been described [18 , 19 ].

Sample collection and preparation
Human anticoagulated whole blood was obtained from 12 different healthy donors. Peripheral polynuclear granulocytes were separated by density-gradient centrifugation and an additional sedimentation step (6% dextran) to remove contaminating erythrocytes. Isolated neutrophils were resuspended in RPMI 1640 supplemented with 10% fetal calf serum (FCS; Gibco, Santa Clara, CA). The purity of isolated granulocytes was >90%, as assessed by fluorescence labeling with the anti-CD66b mAb 80H3 (Immunotech, Marseille, France). To block nonspecific Fc receptor-mediated binding of test mAbs in experiments performed with isolated granulocytes, purified human immunoglobulin G (IgG; 500 µg/ml; Sigma, St. Louis, MO) was added to the cell suspension.

Immunoflourescence-staining procedure
Immunofluorescence labeling was performed by incubation of whole blood (100 µl) or isolated granulocytes (1x105 cells) with at least three different concentrations (0.5, 1, 2 µg/sample) of the anti-LeY mAb ABL 364 or its respective F(ab)'2 fragment for 30 min on ice. After washing in phosphate-buffered saline (PBS) def/10% FCS, cells were stained for 30 min with fluorescein isothiocyanate (FITC)-conjugated F(ab)'2 fragments of sheep anti-mouse IgG3 (Southern Biotechnology Associates, Birmingham, AL). In the case of whole blood, the different leukocyte subpopulations were stained with phycoerythrin (PE)-conjugated mIgG1 anti-CD mAbs specific for CD3, CD14, CD19 (Becton Dickinson, Rutherford, NJ), and CD66 (Monosan, Uden, The Netherlands). After washing and in the case of whole blood samples after lysis of erythrocytes by ammonium chloride, the leukocytes were fixed with 1% paraformaldehyde PBS. Flow cytometric analysis was performed on a FACScan cytofluorimeter (Becton Dickinson). At least 40,000 cells were counted in each sample. In competitive binding experiments, various concentrations (1, 5 µg/ml) of the neoglycoproteins LeY-BSA or LeX-BSA (Chembiomed, Edmonton, Canada) were added to ABL 364-labeled granulocytes, and the decrease in the membrane fluorescence intensity was monitored by fluorescein-activated cell sorter (FACS).

In vitro activation of isolated granulocytes
For in vitro activation, isolated granulocytes (1x106 cells) were suspended in RPMI 1640/10% FCS and incubated with different concentrations (10-9 M–10-6 M) of the chemotactic peptide fMLP (Sigma). After varying periods of incubation at 37°C (5–60 min), the cells were washed, fixed, and stained for FACS analysis.

Immunoprecipitation and immunoblotting
Immunoprecipitation of nonspecific crossreacting antigens (NCAs) was performed with mAb CLB gran/10 recognizing NCA-160/90 (Monosan) and anti-NCA-95 mAb 80H3 (Immunotech). The specificity of both mAbs for the respective glycoproteins has been described [20 ]. Sham precipitates were performed with anti-CD3 mAb (Becton Dickinson). All mAbs were coupled to sheep anti-mIgG, chemically crosslinked to protein A-Sepharose beads (Bio-Rad, München, Germany). Lysis of isolated neutrophils (109 cells) was performed in PBS medium containing 0.5% Nonidet P-40 (NP-40), 5 mM ethylenediaminetetraacetate (EDTA), 1 mM diisopropyl fluorophosphate, and 0.5 mM phenylmethylsulfonyl flouride (Sigma). After a preclearing step with irrelevant mIgG coupled to protein A-Sepharose (Sigma), immunoprecipitation was carried out overnight at 4°C. Thereafter, the samples were run with reduced 5–10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and electrophoretically transferred to nitrocellulose membranes. After blocking with BSA (1% BSA in 10 mM Tris-HCl, 150 mM NaCl, 0.05% Tween 20, pH 8.0), the nitrocellulose sheets were incubated for 1 h with mAb ABL 364 ({approx}10 µg/ml). After incubation with a horseradish peroxidase-conjugated anti-mIgG mAb (Bio-Rad), bound mAbs were detected by chemiluminescence (Amersham, Amersham, England).

Crossed-immunoprecipitation enzyme-linked immunosorbent assay (ELISA)
For crossed immunoprecipitation ELISA, the precleared NP-40 granulocyte extract was exposed to the wells of a microtiter ELISA plate precoated overnight (4°C) with 2 µg/well of anti-CD66 mAbs or isotype control mAbs. The plates were incubated for 2 h at room temperature and washed, and mAb ABL 364 was added at a final concentration of 0.5 µg/well for 2 h. After incubation with peroxidase-conjugated anti-mIgG3 antibody (Southern Biotechnology; 1:1000 in PBS def./10% FCS), the plates were developed using O-phenylenediamine dihydrochloride as substrate (Sigma).


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RESULTS AND DISCUSSION
 
Dual-color flow cytometric analysis of whole blood from 12 healthy volunteers revealed a strong reactivity of peripheral granulocytes with the anti-LeY mAb ABL 364. The reactivity of mAb ABL 364 or its respective F(ab)'2 fragment was restricted to CD66+ granulocytes; CD3+ T-cells, CD19+ B-cells, or CD14+ monocytes showed no significant staining with the anti-LeY-mAb (Fig. 1 ). Comparative binding experiments with LeY-conjugated neoglycoproteins substantiated the expression of LeY on granulocytes. The addition of multivalent LeY-BSA conjugate, but not LeX-BSA, to mAb ABL 364-labeled, granulocytes dose-dependent diminished the fluorimetric signals (Table 1 ). Our findings confirm the previously suggested myeloid lineage-specific expression of the LeY oligosaccharide [16 ] but indicate that the expression of LeY as recognized by mAb ABL 364 is uniquely retained by polynuclear granulocytes.



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  		Figure 1. Representative dual-color fluorescence histograms of a healthy donor after staining of whole blood cells with anti-LeY mAb ABL 364. A, cell control; B, control mIgG1-PE vs. control mIgG3 + anti-IgG3-FITC; C, anti-CD3-PE vs. ABL 364 + anti-IgG3-FITC; D, anti-CD14-PE vs. ABL 364 + anti-IgG3-FITC; E, anti-CD19-PE vs. ABL 364 + anti-IgG3-FITC; F, anti-CD66-PE vs. ABL 364 + anti-IgG3-FITC.


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  		Table 1. Competition of LeY- or LeX-conjugated neoglycoproteins for binding of mAb ABL364 to the granulocyte membrane surface

To attain their fully functional potential, neutrophils respond to a variety of stimuli with exocytosis of their intracellular granules. This process is associated with an enhanced expression of several cell surface glycoproteins, including receptors involved in the cytoadhesive properties of neutrophils [21 ]. To address the question whether the process of granulocyte activation may be accompanied by alterations in the expression of LeY, isolated neutrophils were stimulated with the chemotactic peptide fMLP before the cytofluorometric determination. After challenge with fMLP within a concentration range of 10-9 M–10-6 M, there was a gradual up-regulation of granulocyte LeY expression. Maximum augmentation was obtained at an activator concentration of 10-7 M (Fig. 2A ). The increase in LeY was observed within a few minutes after stimulation and reached its peak (three-fold increase above unstimulated control) after 30 min of stimulation (Fig. 2B) . A similiar augmentation in the LeY determinant was not observed when granulocytes were incubated with mAb ABL 364 in the absence of any additionally activator, indicating that mAb ABL 364 does not exert any direct granulocyte activation activity, as has been observed for other anticarbohydrate mAbs [22 ].



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  		Figure 2. Increased expression of LeY reactivity after stimulation of isolated granulocytes with fMLP. A, Dose-response curve of LeY antigenic reactivity after stimulation with varying concentrations of fMLP (10-9–10-6 M); B, kinetic of the observed augmentation of the granulocyte LeY expression. {circ}, Granulocyte LeY after activation with fMLP (10-7 M); •, granulocyte MFI obtained after staining with mAb ABL 364 without activation. Data shown are expressed as mean ± SD of three independent experiments.

We next investigated the possible carrier structure of the LeY oligosaccharide. Based on previous findings that the LeY glycodeterminant is attached to carcinoembryonic antigen (CEA) [23 ], we considered that granulocyte LeY may be presented by NCAs. As a group of CEA-related glycoproteins, NCAs have been summerized into the cluster designation of the CD66 cluster. The assumption that NCAs are the presenting proteins for granulocyte LeY is supported by several findings. First, NCAs represent a group of highly glycosylated proteins with a high degree of structural identities to CEA [24 ]. Second, similar to the observed increase in the LeY expression, the CD66 antigens are upregulated upon granulocyte activation in vitro [25 ]. Third, NCAs have been previously described as presenter molecules of various carbohydrate groups of the Le family, including LeX and sLeX [20 , 26 ].

To estimate the expression of the LeY oligosaccharide on NCAs, we performed a series of immunoprecipitation experiments to determine whether anti-LeY mAb ABL 364 would bind to detergent-solubilized neutrophil membrane extracts precipitated by mAb CLB gran/10 (which recognize NCA 160/90) or mAb 80H3 (defining NCA-95). After SDS-PAGE, followed by immunoblotting, ABL 364 stained the 160/90-kD protein bands precipitated by mAb CLB gran/10 and the 95-kD protein band precipitated by mAb 80H3 (Fig. 3 ). However, the reactivity toward the 80H3-precipitate was weak compared with the CLB gran/10 precipitate. Similar data were also obtained in a crossed-immunoprecipitation ELISA (unpublished results), therefore confirming the previously suggested differences in the glycosylation pattern of various members of the CD66 antigens [27 ].



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  		Figure 3. Immunoblot of the granulocyte NCAs obtained after precipitation with mAb 80H3, mAb CLB gran/10, or control (anti-CD3) mAb and probed with mAb ABL 364. The gel was run under reduced condition. The relative positions of the Mr markers are indicated at left (x1000).

Our observation of an augmented expression of the LeY determinate during granulocyte activation strengthens the possibility that the LeY hapten plays a role in the physiological functions of neutrophils. In particular, our finding of an expression of the LeY determinant on members of the CD66 adhesion molecules supports the view of an involvement of the LeY carbohydrate in the process of cellular cytoadhesiveness [11 ]. This might take place via carbohydrate-carbohydrate interaction, i.e., the recently proposed interaction between LeY and the H antigen [13 , 28 ] or similar to the sLeX structure, via binding to a perhaps unknown cellular lectin receptor.


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ACKNOWLEDGEMENTS
 
This work was supported by grant L 0033/ MED (M. D.) from the "Österreichischen Fond zur Förderung der wissenschaftlichen Forschung," Vienna, Austria.

Received July 21, 1999; revised March 30, 2000; accepted April 10, 2000.


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