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Department of Immunology, Erasmus University, Rotterdam, The Netherlands
Correspondence: Prof. Dr. H. A. Drexhage, Dept. of Immunology, Lab. Ee 838, Faculty of Medicine, Erasmus University Rotterdam, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: cellular aggregates • BB-DP rat
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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One of the eye-catching features of veiled cells in lymph, particularly evident after the application of a skin sensitizer, is their ability to form cellular aggregates or homotypic clusters [13 ]. Similarly, clusters of Langerhans cells (LCs) present in lymphatic vessels of the dermis have been described [14 , 15 ]. With respect to the formation of such homotypic clusters of DCs, the question was raised whether such cluster formation is just an accidental encounter of migrating cells, or whether it plays a physiological role in the function of the cells.
Various stimuli have been described to enhance the formation of
homotypic clusters of DCs, amongst which antibodies (Abs) to CD43
[16
17
18
19
20
21
]. CD43 (sialophorin/leukosialin) is a
sialoglycoprotein, primarily recognized as an anti-adhesion molecule
due to its negative charge and long unfolded structure [for review see
ref. 22
]. Treatment of human DCs with anti-CD43 Ab causes removal of
CD43 from the surface of DCs, resulting in an enhancement of DC
homotypic clustering [18
, 19
]. It is
interesting that Abs to CD43 also induce a phenotypic and functional
maturation of the cells as measured by an augmentation of their
expression of adhesion and costimulatory molecules and Ag-presenting
function of the Ab-treated cells [18
, 19
].
Bacillus Calmette-Guérin (BCG), tumor necrosis factor 
(TNF-) and Abs to CD44 had similar effects on maturation of DCs
[16
, 17
, 20
, 21
].
Incubation of DCs with RANKL, a new member of the TNF-receptor family,
also stimulated the allostimulatory capacity of DC and their cluster
formation, but in the absence of a modulation of expression of adhesion
and costimulatory molecules [23
].
Recently, Ag transfer from one DC to the other has been recognized as another mechanism to enhance the T cell stimulatory function of DCs: the Ag-presenting and T cell-stimulatory capacity of mouse DCs that had acquired Ag from Ag-pulsed DCs was much higher than that of DCs that had been pulsed with Ag alone [24 ].
Collectively, these data indicate that homotypic interactions of DCs may form a mechanism to stimulate the accessory cell function of the cells by (1) mutual delivery of maturation signals, and (2) by transfer of Ag between the cells. Therefore, we have studied the formation of homotypic clusters of splenic DCs from the Wistar rat under various conditions (e.g., increasing cell densities, anti-CD43 treatment), and investigated (after the cells had engaged in clustering) the changes in phenotype (focusing on the expression of CD80 and CD86) and in accessory cell function using a syngeneic (syn) mixed lymphocyte reaction (MLR). Syn MLRs were used because DCs in particular are capable of driving autologous/syngeneic MLRs, and also because such assays are considered to reflect the capability of DCs to expand regulatory/suppressor T cells [25 26 27 ] [see further below, studies on the biobreeding diabetes-prone (BB-DP) rat]. Finally, we investigated the transfer of Ag from bovine serum albumin-fluorescein isothiocyanate (BSA-FITC)-pulsed DC to unpulsed DCs during homotypic clustering.
Several years ago we reported that homotypic cluster formation is disturbed in monocyte-derived DCs from patients with Graves’ disease and patients with diabetes [28 , 29 ]. Yet the importance of this defect was and still is difficult to interpret. BB-DP rats are an excellent model for autoimmune diabetes and autoimmune thyroiditis. We previously described that splenic DCs of the BB-DP rat are relatively immature cells, showing a low accessory cell function and a low expression of costimulatory molecules [27 ]. This relative immaturity of BB-DP splenic DC had negative consequences for the stimulation of RT6+ T cells, the regulator/suppressor T cells of this animal model [27 ]. In addition, in this study we have investigated the homotypic cluster capability of splenic BB-DP DCs, and the consequences of this process for the maturation of the DCs of this autoimmune-prone animal by determining their T cell stimulatory capacity in syn MLR and their phenotype. The effect of anti-CD43 Ab treatment on cluster capability and T cell stimulatory capability in syn MLR of BB-DP DC was also investigated.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-colloid antibodies detectable in
serum; 70–80% of the rats become diabetic. BB-DP rats were tested
daily for glucosuria (Gluketur test sticks; Boehringer Mannheim,
Almere, The Netherlands). The age of the rats varied from 3 to 20 weeks
and for all experiments age- and sex-matched BB-DP and Wistar rats were
used.
Cell preparations (DCs, macrophages, T cells, B cells)
Splenic DCs were enriched as described before
[27
]. Briefly, spleens from BB-DP and Wistar rats were
minced and digested for 1 h at 37°C in RPMI 1640 medium
(GIBCO-BRL Life Technologies, Breda, The Netherlands) with 25 mM
glutamax-1, 25 mM HEPES (referred to as RPMI+) additionally
containing 125 U/mL collagenase (type III; Worthington Biochemicals)
and 0.1 mg/mL DNase (type 1, Boehringer). The remaining tissue was
teased through a 105-µm filter, and the erythrocytes were removed by
lysis. Finally, the separated cells were washed and cultured in
RPMI+ supplemented with 10% inactivated fetal calf serum
(FCSi), penicillin (100 U/mL; Seromed, Biochrom, Berlin, Germany), and
streptomycin (0.1 mg/mL; Seromed). After an overnight culture period in
culture flasks (Costar Europe, Badhoevedorp; 37°C, 5%
CO2 incubator), DCs were isolated from the nonadherent
cells by using a 14.5% (wt/vol) Nycodenz (Nycomed Pharma, Oslo,
Norway) density gradient (800 g for 20 min). Low-density
cells were collected from the interphase and washed. This cell fraction
demonstrated in >90% of the cells a dendritic morphology, a strong
MHC II expression, and a weak acid phosphatase (AP) activity in both
rat strains.
After removal of nonadherent cells for isolation of DCs (see above),
splenic macrophages (sM
) were obtained by collecting the adherent
cell fraction with a rubber policeman. Resident peritoneal (p)M were
harvested by lavage of the peritoneal cavity with 10 mL ice-cold
phosphate-buffered saline (PBS; pH 7.4) containing 50 U/mL heparin.
Cells were washed and, when present, erythrocytes were lysed. Splenic
adherent and peritoneal fluid cells from both rat strains contained,
respectively, 65–70% and 50-63 ED2+ and AP+
cells as determined on cytospin preparations.
Wistar T cells (needed for the syn MLR, see below) were enriched using a nylon wool column. In short, spleens were minced and teased through a 105-µm filter, and the erythrocytes were removed by lysis. Cells were washed and loaded onto a nylon wool column (3 g, Polyscience, Eppelheim, Germany) packed into a 60-mL plastic syringe. After 1 h in a 5% CO2 incubator at 37°C, cells were harvested by collecting the effluent cells, which contained 80–90% CD5+ T cells as determined by FACS analysis.
B cells were obtained by disruption of the nylon wool to elute the
loosely adherent cells, followed by incubation for 1 h under
adherent conditions at 37°C to deplete for sM. Finally,
nonadherent cells were removed; this cell fraction contained 41–54%
OX33+ B cells as determined by FACS analysis (FACScan,
Becton Dickinson, Sunnyvale, CA).
Homotypic cluster assay
DCs were plated in flat-bottom 96-well plates (Nunc) in the
majority of experiments at a concentration of 1 x 105
cells/200 µL/well. In a few experiments we varied cell numbers (0.5,
1, and 2 x 105 cells) per either a fixed fluid volume
(200 µL/well) or a volume of 50, 100, or 200 µL/well, respectively.
After various time points, formed clusters were randomly counted
independently by two investigators, using an inverted microscope, and
values were expressed as the number of clusters per six microscopic
fields (x250). A cluster was defined as an aggregate of four or more
cells.
The size of formed clusters with DCs was also determined. Images of clusters were recorded via an inverted microscope (Axiovert, Zeiss) attached to a video camera (Sony) and stored in a computer (Acorn Computers, Cambridge, UK). The images were analyzed with the use of a Vidas RT system (Kontron Elektronik/Carl Zeiss, Weesp, The Netherlands) and expressed in pixels [1500 pixels (2–3 cells)]. Cluster formation with DCs was also studied (1) at 4°C, (2) after fixation of the cells with 1% paraformaldehyde (FACSFIX, Beckton Dickinson, San Jose, CA), and (3) in the presence of Ab against the adhesion molecules CD54 and CD11a (1:50, Serotec) and sialophorin CD43 (1:20, Serotec).
MLR
The accessory cell activity of DCs from BB-DP and Wistar rats
was tested in a syn MLR after overnight clustering using different cell
concentrations (0.5, 1, and 2 x 105 cell/well), fluid
volumes (50, 100, and 200 µL/well), or with the addition of Ab
against CD43 (1:20). Clustered DCs were washed and resuspended followed
by an irradiation with 2,000 rad. The irradiated Wistar and BB-DP DCs
were added to Wistar T cells (DC/T cell ratio of 1:5 with a fixed
number of 150,000 T cells/well; Wistar T cells can be used with BB-DP
DCs because both animal models share MHC class-II haplotypes
[27
]) in flat-bottom 96-well plates (Nunc).
Subsequently, these syn MLRs were cultured for 4 days in RPMI 1640
containing 50 mM HEPES buffer (GIBCO), 10% FCSi, 110 µg/mL
Na-pyruvate (Merck, Munich, Germany), 5 x 105 M
ß-mercaptoethanol (Merck), and antibiotics. In the MLR, T cell
proliferation was measured via tritiated thymidine (3H-TdR)
incorporation (0.5 µCi/well during the last 8 h of total culture
period). Finally, cells were harvested on filter papers, and
radioactivity was counted in a liquid scintillation analyzer (LKB
Betaplate, Wallac, Turun, Finland).
Antigen transfer
Ag transfer experiments were performed according to Knight et
al. [24
] with minor modifications. In short,
106 DCs were pulsed with Ag by incubating for 2 h with
0.5 mg/mL of BSA-FITC (Sigma) at 37°C. After a thorough wash,
0.5 x 105 pulsed DCs were added to the same number of
unpulsed DC per well in a flat-bottom 96-well plate, and either
directly fixed in 1% formaldehyde (t = 0 h) or
incubated for 3 and 16 h and thereafter fixed. As a control, the
different cell suspensions were incubated separately. After fixation,
the cells were analyzed by FACS for the presence of BSA-FITC.
FACS analysis
For FACS analysis, formed clusters were disrupted by gentle
pipetting. The homotypic clusters could easily be disrupted by this
procedure, and only minimal forces were needed to separate the cells.
The single cells were added to round-bottom 96-well plates (Nunc) at a
concentration of approximately 1 x 105 cells/well and
washed twice in PBS/0.5% BSA/20 mM sodium azide. Pelleted cells were
resuspended in 20 µL solution with labeled primary Ab, incubated for
10 min, followed by two washing steps. The following mAbs were used for
cell staining: anti-MHC class II conjugated to phycoerythrin (PE;
1:400, MRC OX-6, Serotec), anti-B7-1 [1:500, CD80, Research
Diagnostics (RDI)], anti-B7-2 (1:500, CD86, RDI), anti-CD11a (1:10,
Serotec), anti-CD54 (1:50, Serotec), and anti-CD43 (1:100, Serotec).
Using unconjugated antibodies, a second step was incorporated with
rabbit-anti-mouse-FITC Ab (DAKO, Glustrup, Denmark) with 1% normal rat
serum. For cell analysis, 10,000 events were recorded with a FACS. Dead
cells, recognized by their uptake of propidium iodide and their
specific forward- and side-scatter pattern, were excluded from
analysis. For determination of background staining, cells were
incubated with either labeled irrelevant Ab or with secondary Ab.
Statistical analysis
The results are presented as means ± SEM.
Statistical analysis of the data was performed with the Mann-Whitney
U test or Wilcoxon’s test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In a separate small series (n = 3) of experiments the
formation of homotypic clusters of DCs was compared to that of other
relevant APC populations, such as splenic macrophages (sM),
peritoneal M (pM), and B cells. Maxima were again reached at
3 h, yet the number of homotypic clusters was considerably smaller
compared with splenic DCs. Splenic M [105 clusters, mean, per six
microscopic fields x250, standard deviation (SD) 15] were
more potent in cluster formation than pM (54 clusters,
SD 2). B cells had the lowest ability to aggregate
homotypically (34 clusters, SD 5).
Effect of homotypic cluster formation of Wistar DCs on their APC
function
To obtain increasing numbers of DC that had engaged in cluster
formation, the cluster assays were first carried out under conditions
of increasing cell densities in a fixed concentration of culture fluid
per well, i.e. 200 µL (Table 1A
). This indeed resulted in an increase in the number and size of
the formed clusters (Table 1A)
. After this increased clustering DCs
were tested for their T cell stimulatory capacity in a syngeneic (syn)
MLR. It appeared that DC populations that had undergone an enhanced
clustering due to increased densities of the cells also had augmented
their accessory cell function in synMLR (Table 1A)
. Table 2
shows that the enhanced DC-DC clustering in the fixed fluid volume
with increasing DC densities also resulted in an increase in the
expression of CD54, CD80, and CD86 on the cells. In addition, there was
a decrease in the expression of CD43. There was no effect of intense
homotypic clustering on MHC class II and CD11a expression (data not
shown).
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Effect of anti-CD43 Ab treatment of Wistar DCs on homotypic cluster
formation
Treatment of Wistar DCs with anti-CD43 Ab increased the number of
homotypic clusters (P < 0.03 on t = 3
and 16 h for Wistar DCs, Fig. 3
). Anti-CD43 Ab treatment also increased the size of the clusters
at t = 3 h of the culture (Fig. 4
). Treatment of DCs with normal mouse serum or isotype control
antibodies (OX-19, a pan T cell marker) had no effect on the clustering
(data not shown). Enhanced cluster formation after anti-CD43 treatment
coincided with a slightly enhanced accessory cell function of the
Wistar splenic DCs in syn MLR, the cpm in the MLR was 23.548 ±
12.736 in the absence of anti-CD43 (DC/T cell ratio 1:5), whereas in
the presence of anti-CD43 these incorporations were 28.194 ±
11.389 (n = 3).
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The number of homotypic clusters formed by such splenic DCs of the BB-DP rat were significantly lower than those of the Wistar rats for t = 1–4 h (Fig. 1) . In addition, the size of the clusters formed by BB-DP DCs were smaller compared with those of Wistar DCs (Fig. 4) . These differences in the number and size of clusters between Wistar and BB-DP DCs were observed for all age groups studied, i.e. varying from 3–20 weeks, thus before the presence of cellular infiltrations in the thyroids or in the islets of the BB-DP rat [30 ].
With regard to clustering of DC under conditions of increased cell density per fixed volume (Table 1A) or under conditions of a higher number of DCs per well in a fixed density (Table 1B) , a modest (but not significant) improvement of the accessory cell function of BB-DP splenic DCs was observed after more intense BB-DP DC-DC clustering. However, levels of clustering, and in particular levels of T cell-stimulating capability of Wistar splenic DCs, were far from reached (Table 1) . There was also an up-regulation of CD54, CD80, and CD86, and a down-regulation of CD43 after enhanced clustering of BB-DP DC (Table 2) . Yet, an up-regulation of CD80 and a down-regulation of CD43 to the level of that of Wistar DCs was also not achieved after this artificially in vitro enforced increase in homotypic clustering of BB-DP DCs.
Treatment of BB-DP DCs with anti-CD43 Ab did clearly increase the number of homotypic clusters on t = 1–3 and 16 h. In fact, the defects in homotypic clustering of BB-DP DCs were completely restored at t = 2–4 h when compared to Wistar DCs (Fig. 3) . At 16 h of culture, BB-DP DCs even formed significantly more clusters than Wistar DCs under these experimental conditions (P < 0.02, n = 8, Fig. 3 ). Yet the defective T cell stimulatory capacity of BB-DP DC was, although somewhat improved, not restored to the level of Wistar DCs: after clustering with 0.5 x 105 cells in the absence of anti-CD43 the cpm in the MLR was 975 ± 400 (DC/T cell ratio 1:5), whereas in the presence of anti-CD43 these incorporations were 2.269 ± 85 (n = 3).
Ag transfer during homotypic cluster formation was also studied with splenic DCs from the BB-DP rat. For all time points similar data were obtained as described for Wistar splenic DCs (see above).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and B cells were able to form homotypic clusters too, but our studies
showed that DCs formed more rapidly more numerous and larger clusters. Another functional consequence of homotypic cluster formation identified in our studies was the transfer of Ag between clustering DCs. Knight et al. demonstrated the passing of BSA-FITC from pulsed to unpulsed DCs after overnight culture and its relevance for optimizing T cell stimulatory capacities [24 ]. We could confirm such transfer of Ag (BSA-FITC) during homotypic clustering of DCs, and Ag transfer was already evident 3 h after coculture of pulsed and unpulsed DCs. According to Knight et al. the passage of Ag also takes place without physical cell-cell interactions (putatively via exosomes), but the authors found its effect on the accessory cell function only optimal after physical contacts between the DCs [24 ]. This supports our concept that homotypic clustering is likely involved in the process of antigen-passage-induced maturation reported by Knight et al.
The formation of homotypic clusters by DCs is an active process, since low temperature or fixation with paraformaldehyde strongly inhibited DC-DC aggregation (this study). Adhesion molecules, known from DC-T cell interactions [31 ], also played a role in homotypic DC interactions, since cluster formation was blocked by Ab against CD11a and CD54 [this report, see also ref. 32 ].
It is interesting that a recent report [33 ] describes that transforming growth factor ß-induced generation of Langerhans cells from their precursors also involves homotypic cell cluster formation, and that this cluster formation could be inhibited by monoclonal antibodies to constitutively expressed adhesion molecules, which resulted in an inhibition of Langerhans cell generation [33 ].
In vivo, homotypic cluster formation is particularly evident in the early phases of inflammation [34 , 35 ], and in lymph during the migration of the cells to the draining lymph nodes [13 14 15 ]. If homotypic cluster formation is a mechanism for DCs to mature and to transfer Ag, how does such a mechanism fit into the presently accepted concept of antigen-uptake by tissue DCs and their maturation during migration after antigenic stimulation? Tissue DCs have been reported to lose their migratory ability upon stimulation with, for example, bacteria. They become strongly adherent under such circumstances, and produce large quantities of chemokines, some of which are attractive for DCs [36 ]. This will result in a local accumulation and homotypic clustering of newly-arrived, non-Ag-pulsed DCs with Ag-pulsed DCs, making possible the Ag-transfer and maturation of cells described here. Several studies indeed report the influx of new DCs as a first event in the induction of an immune response; e.g., upon local challenge of the rat lung with different agents, DCs were the first cells to appear within the airway epithelium and a maximum number of DCs was reached, exceeding three times the steady-state population [34 , 35 ]. In mice, DC precursors were recruited to heart and kidney after systemic administration of lipopolysaccharide [37 ], and in the rat brain, infiltrating DCs were observed in delayed-type hypersensitivity lesions [38 ]. In the human LCs accumulate in the dermis after intradermal injection of granulocyte-macrophage colony-stimulating factor [39 ].
Homotypic interactions of DCs may also take place in the lymph
[13
14
15
] and the T cell area of the draining lymph
nodes. At these spots, further maturation and Ag-transfer may occur.
Local lymph nodal DCs secrete chemoattractants for DCs
[40
]. In addition, it has been shown that DCs migrating
in lymph nodes were able to transfer Ag to recipient DCs in
vivo [41
]. Passing of Ag was also suggested from
Ag-pulsed lymphoid (CD8+) DCs to host lymphoid DCs after
injection [42
].
Homotypic interactions of monocyte-derived DC are hampered in patients with recent onset type 1 diabetes [29 ], in patients with recent onset thyroid autoimmune disease [28 ], and even in thyroid autoantibody-positive individuals at risk of developing thyroid autoimmune disease [43 ]. This report shows that also in an animal model of such diseases, i.e. the BB-DP rat, homotypic DC-DC cluster formation is impaired, actually already before the development of the disease. The clustering defect in this autoimmune-prone animal was closely correlated with the poor maturation state and maturation potential of the DCs. It had no effect on Ag transfer. In the human and in the mouse this maturation defect of APC has been suggested to have implications for tolerance induction [25 , 26 , 28 , 29 , 43 44 45 46 47 48 ]. In the BB-DP rat there is indeed experimental evidence that this is the case: the relatively immature splenic DCs of this animal are less able to stimulate RT6+ T cells, i.e., the regulator/suppressor T cell population of this rat model.
The clustering defect of BB-DP splenic DCs described here is specific for the diabetes-prone subline of the rat strain; the diabetes-resistant subline does not show this abnormality [27 ]. This might implicate that T cells themselves (and perhaps in particular the RT6+ T cells) influence the clustering potential of DCs, since the BB-DP rat is lymphopenic particularly for RT6+ T cells [49 ]. It is also possible that the lyp-gene of the BB-DP rat directly influences the clustering behavior of the DCs [50 ].
With regard to a possible restoration of the splenic BB-DP DC defect, our data show that an enforced clustering, due to higher densities or numbers of BB-DP DCs per well, was able to induce some DC maturation: a very modest increase in T cell-stimulating capacity in syn MLR and an increase in CD80 and CD86 expression were found. However, a complete restoration of mature marker expression and of accessory function up to the level of that of Wistar rat DCs was far from accomplished via this mechanism. It is interesting that incubation with anti-CD43 Abs restored the defective clustering behavior of BB-DP DCs in full, and after overnight culture BB-DP DCs even formed more clusters than Wistar DCs. The anti-CD43 treatment did, however, also not result in a noteworthy correction of the defective T cell stimulatory capacity of the BB-DP DCs.
In conclusion, homotypic clustering of DCs is a close correlate of the maturation state of the DCs. It is also a likely mechanism for DCs to further mature, and enhance their function as immune accessory cells. The impaired homotypic cluster formation of DCs in BB-DP rats (this report), in patients with Graves’ disease [28 ] and in patients with diabetes [29 ], most likely represents an abnormally low state and capability of maturation of the APC. Our previous report [27 ] shows that this has consequences for tolerance induction, at least in the BB-DP rat.
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ACKNOWLEDGEMENTS |
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Received July 13, 2000; revised October 8, 2000; accepted November 7, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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cooperate in the generation of dendritic Langerhans cells Nature 360,258-261[Medline]
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