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1
,
*
Department of Dermatology and
Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg, Erlangen, Germany; and
Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, has been identified on human T cells,
immature thymocytes, and a subset of B cells. We have found that SLAM
is expressed on mature but not immature dendritic cells (DC). However,
the SLAM-associated protein, is missing in DC. SLAM surface
expression is strongly up-regulated by IL-1
. Addition of IL-1 to
the DC maturation mixture also increases the stimulatory properties of
DC. These findings provide a new marker for DC maturation and help to
explain two areas of DC biology. First, SLAM is a receptor for the
measles virus, previously shown to infect DC. Second, SLAM could
possibly contribute to the enhanced immunostimulatory functions of DC
that are observed following the addition of
IL-1. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cardinal properties of the myeloid lineage-derived DC include the following functional and phenotypical characteristics: 1) the ability to take up, process, and present Ags; 2) the ability to migrate and at the same time mature; and 3) the ability to interact with, stimulate, and direct T lymphocyte responses (4, 5). Functional, mature DC are derived in vivo or in vitro from circulating precursor cells after a period of maturation. During this period, manifold activities on the level of gene regulation take place within the precursor cells, which ultimately result in the generation of mature DC. In addition to their functional qualities, DC are also characterized by the expression of a specific array of marker molecules. These include the accessory/costimulatory gene products CD40, CD80, CD86 as well as MHC class I and II molecules and CD83 (1, 6, 7).
To become potent T cell stimulators, DC have to mature. Immature DC, which reside in the peripheral tissue, capture and process Ags and subsequently migrate to secondary lymphoid organs, whereas mature DC present processed peptides very efficiently to rare Ag-specific T cells (8). During this maturation, a variety of different DC-specific gene products are up-regulated. This includes adhesion and costimulatory molecules, MHC class I and class II molecules, and CD83.
Apart from the interaction between the TCR and MHC-peptide complex, also costimulatory signals are crucial to potently stimulate T cells. These include molecules expressed on the cell surface of T cells such as CD28 and ICOS, as well as the recently identified novel signaling lymphocytic activation molecule (SLAM), and their corresponding receptors on APCs (9). SLAM, which has also been designated CDw150 or IPO-3 (10, 11), belongs to the CD2 subfamily of the Ig supergene family (12). The potential biological importance of SLAM is highlighted by the finding that mutations or deletions of a SLAM-associated protein, SAP (also called SH2D1A or DSHP), causes severe illness, the X-linked lymphoproliferative disease (13, 14, 15). Furthermore, SLAM has very recently been identified as a cellular receptor for the measles virus (16).
CD45RO+ T cells, immature thymocytes, and subsets
of B cells express SLAM (12) and its expression is rapidly
up-regulated after B and T cell stimulation (17). The
engagement of SLAM can trigger T cell proliferation, can trigger
production of IFN- (18, 19, 20, 21), and can augment
DC-dependent spread of HIV (22). Different isoforms of
SLAM, including a soluble, secreted, and a cytoplasmic form, have been
identified (12, 18). Furthermore, SLAM has been shown to
be its own ligand (12, 17). The soluble isoform of SLAM
can be detected in serum and synovial fluid and induces proliferation
and Ig synthesis in B cells (12, 17).
However, SLAM has not been studied on the critical DC system of APCs, where it would act as the required ligand for SLAM signaling in B and T cells. In this study, we report that SLAM is expressed upon DC maturation, although in the absence of SAP. We present evidence that SLAM can possibly contribute to the capacity of DC to stimulate lymphocytes dependent on their maturation stage and characterized the induction of SLAM expression which might help to further understand the interaction between DC and T cell.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640 (BioWhittaker, Walkersville, MD), supplemented with glutamine (300 µg/ml; BioWhittaker), penicillin/streptomycin (20 µg/ml), 10 mM HEPES (pH 7.5; Sigma, St. Louis, MO), and 1% of heat-inactivated (56°C for 30 min) human plasma from a single AB donor, obtained from the Department of Transfusion Medicine (Erlangen, Germany) was used as standard medium.
Generation of DC
PBMC (5 x 107) isolated from buffy
coats were sedimented in Ficoll-Hypaque (Pharmacia Biotech, Uppsala,
Sweden) and seeded onto an IgG-coated (10 µg/ml; Sigma) 100-mm
culture dish and incubated at 37°C in 5% CO2.
After 1 h, the nonadherent cell fraction was recovered, and the
adherent cells were further incubated for 7 h in medium containing
1% human plasma. Then, a second nonadherent cell fraction was removed.
The first step of DC differentiation (i.e., conversion of adherent
monocytes to immature DC) was induced by adding the cytokines GM-CSF
(800 U/ml; Novartis Research Institute, Vienna, Austria) and IL-4 (1000
U/ml; Genzyme, Cambridge, MA) to the medium containing 1% human
plasma. Cytokines were added again on day 3 in 5 ml fresh medium
(containing 4000 U GM-CSF and 5000 U IL-4) per dish. On day 5, all
nonadherent cells were collected, counted, and transferred into new
culture dishes at a density of 0.3–0.5 x
105 cells/ml. For the second step of DC
differentiation (i.e., maturation of immature DC into fully mature and
stable DC), the medium containing 1% human plasma, GM-CSF (400 U/ml),
IL-4 (500 U/ml), TNF-
(25 ng/ml; Boehringer Ingelheim, Vienna,
Austria), and PGE2 (1 ng/ml; Cayman Chemicals,
Ann Arbor, MI) was supplemented either with or without 1 ng/ml IL-1
(Sigma). For certain stimulation studies, agonistic anti-CD40 mAbs
(Cymbus Biotechnology, Chandlers Ford, U.K.) and anti-SLAM mAbs A12
(DNAX, Palo Alto, CA) (11) were added simultaneously to
the maturation mixture composed of TNF- and
PGE2 with or without IL-1 (1 ng/ml).
In some experiments, DC were cultured either in the presence of an
IL-1-neutralizing Ab (catalog no. 0796; Immunotech, Marseilles,
France) or in the presence of the human IL-1 receptor antagonist
(IL-1RA; R&D Systems, Abingdon, U.K.) to investigate the influence of
IL-1 on the SLAM expression. The neutralizing Ab or the IL-1RA was
added 15 min. before the maturation mixture was added to the cell
cultures. Cells were then cultured as described above.
FACS analyses
Phenotypic analyses of cells (1 x 105) were performed by flow cytometry using saturating concentrations of the following mAbs: anti-SLAM (DNAX), CD83 (Immunotech), CD54 (Dianova, Hamburg, Germany), and CD14 and CD80 (BD PharMingen, Hamburg, Germany). The isotype controls IgG1a, IgG2a, and IgG2b were obtained from BD Biosciences (Mountain View, CA) and were run in parallel. Ten thousand cells were analyzed on a FACScan (BD Biosciences). Nonviable cells were gated out on the basis of their light scatter properties.
RNA isolation and RT-PCR
Cultured cells were harvested and washed in PBS at different
time points of DC generation. RNA of each sample was prepared using the
acidic phenol extraction method. Samples were stored at -80°C until
used. Reverse transcription was performed using the Superscript system
(Life Technologies, Eggenstein, Germany) according to manufacturer’s
instructions. Two to 4 ng of the resulting cDNA were used as template
and amplified with Taq polymerase (PerkinElmer, Langen,
Germany). A RT-PCR for -actin and a negative control with no cDNA
template were run in parallel with each experiment. To detect isoforms
of SLAM and SAP, 40 cycles were performed (initial denaturation at
94°C for 2 min, 30 s at 94°C, 30 s at 55°C, and 1 min
at 72°C). The following primers were used: for membrane-bound SLAM:
sense, 5'-ATC ACT GGA GAA CAG TGT-3' and antisense, 5'-CCC AGC ATA CAC
TGC CC-3'; for soluble SLAM: sense, 5'-ATC ACT GGA GAA CAG TGT-3' and
antisense, 5'- TTC GTT TTA CCT GAG GGG TCT G-3'; for SAP: sense, 5'-GCC
TGG CTG CAG TAG CAG CGG CAT CTC CC-3' and antisense, 5'- ATG TAC AAA
AGT CCA TTT CAG CTT TGA C-3'; for the CD3-
chain: sense, 5'-GAA GAT
CTA GAG TGA AGT TCA GCA GGA G-3' and antisense, 5'-GCT CTA GAT
TAG CGA GGG GGC AGG GCC-3'; and for -actin: sense, 5'-GAA CTT TGG
GGG ATG CTC GC-3' and antisense, 5'-CGG GAA ATC GTG CGT GAC AT-3'. PCR
products were electrophoresed using a 1% agarose gel and visualized
with ethidium bromide.
Allogeneic MLR
CD4+ T cells (2 x
105/well) were negatively isolated using a CD4 T
cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) from
buffy coats and were stimulated with mature allogeneic DC, which were
either matured in the presence or absence of IL-1. T cells and DC
were cocultured for 4 days in 200 µl RPMI 1640 supplemented
with 5% human serum from a single AB donor in 96-well cell culture
dishes. Then, cells were pulsed with
[3H]thymidine (1 µCi/well; Amersham,
Braunschweig, Germany) for 8–16 h. The culture supernatants were
harvested onto glass fiber filters using an IH-110 harvester (Inotech,
Dottikon, Switzerland) and filters were counted in a 1450 microplate
counter (PerkinElmer Wallac, Gaithersburg, MD).
Allogeneic cord-blood MLR
Cord-blood PBMC, obtained from human cord blood of healthy
donors after informed consent was given, were isolated by
centrifugation over a density gradient (Lymphoprep; Nycomed Pharma,
Oslo, Norway). On day 6, DC were matured with the maturation mixture in
the presence or absence of IL-1. Cells which did not receive the
maturation stimulus remained immature and were used as controls. On day
7, mature and respectively immature DC were harvested, washed twice,
and added in graded doses to 2 x 105
allogeneic T cells/well in 96-well flat-bottom plates and coincubated
for 4–5 days in RPMI 1640 supplemented with gentamicin, glutamine, and
5% heat-inactivated human pool serum. The proliferation was determined
by addition of [3H]thymidine (4 µCi/ml final
concentration) for the last 12–16 h of culture.
Induction of peptide-specific CTL
Purified CD8+ T cells were obtained by
magnetic cell sorting using CD8 microbeads according to the
manufacturer’s instructions (Miltenyi Biotec). Autologous DC from
HLA-A2.1+ healthy donors were either pulsed with
HLA-A2.1-restricted influenza matrix peptide (GILGVVFTL, purchased from
Clinalfa, Läufelfingen, Switzerland; 10 µg/ml for 4 h at
37°C at 1 x 106 DC/ml) or left untreated.
These cells were then incubated with T cells at a DC:T cell ratio of
1:10 for 7 days without the addition of any cytokines.
IFN--producing effector T cells were then quantified by ELISPOT
analyses. Briefly: 5 x 104/well
CD8+ T cells were added in triplicates to
nitrocellulose-bottom 96-well plates (MAHA S4510) precoated with the
primary anti-IFN- mAb (1-D1K; Mabtech, Stockholm, Sweden) in 50
µl ELISPOT medium (RPMI 1640 containing 5% heat-inactivated human
serum)/well. After addition of influenza matrix peptide (10 µg/ml)
and incubation for 20 h, wells were washed six times, incubated
with the biotinylated IFN--specific mAb (7-B6-1; Mabtech) for 2
h, washed, and stained with a Vectastain Elite kit (Vector
Laboratories, Burlingame, CA). Spots were evaluated and counted using a
special computer-assisted video imaging analysis system (Carl Zeiss
Vision, Eching, Germany).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate SLAM expression on the cell surface during DC
maturation, we generated DC in vitro following an improved two-step
protocol (23). Briefly, the DC generation includes a first
step, whereby Ig-adherent monocytes are converted into immature DC
under the aegis of GM-CSF and IL-4 over 4 days, followed by a final
maturation step induced by a mixture composed of TNF- and
PGE2 with or without IL-1. The generated DC
showed all the typical phenotypical and functional properties including
stellate morphology, nonadherence to plastic, up-regulation of MHC I
and II and costimulatory molecules (24), CD83
(25), and intracellular p55 (26), and a very
high capacity to stimulate allogeneic CD4+ and
CD8+ T cell responses as described elsewhere
(23, 27).
To follow SLAM expression during DC maturation, FACS analyses were
performed on days 2, 4, and 7 (Fig. 1A
).
DC analyzed on days 2 and 4 represent DC precursors, whereas day 7
analyses represent finally differentiated mature DC. Cells were stained
with mAbs specific for SLAM, CD83, a well-characterized marker for
mature DC, and CD14, the marker for monocytes and macrophages. The FACS
data clearly demonstrated that SLAM was only found on mature DC and was
up-regulated in parallel with the well-characterized DC marker CD83. In
contrast, DC precursors that were analyzed on days 2 and 4 expressed
neither SLAM nor CD83 (see Fig. 1A). To exclude the
possibility that contaminating T cells were responsible for the SLAM
expression, RT-PCR analyzes were performed. The absence of T cells in
these DC cultures was confirmed using CD3-
chain-specific primers
(Fig. 1B). In addition DC cultures were analyzed by
two-color FACS using CD3, CD19, CD83, as well as SLAM-specific Abs
(Fig. 1C). These data clearly show that the DC-specific SLAM
expression is not due to a T or B cell contamination. CD83-positive DC
do express SLAM. Taken together, these data demonstrate for the first
time that SLAM is expressed on the cell surface of mature DC but not of
immature DC.
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To identify which SLAM isoforms are expressed in DC, total
cellular RNA from immature and mature DC extracts was analyzed by
RT-PCR. This highly sensitive RNA assay revealed that both
membrane-bound-SLAM and soluble SLAM were expressed in mature DC (Fig. 2, lane 2), but not in
immature DC (Fig. 2, lane 1). These results confirmed the
FACS data. Moreover, the message for the SAP which is associated with
SLAM in T cells (15) could only be detected in T cells
(Fig. 2, lane 4) but not in immature or mature DC (Fig. 2, lanes 1–3). In addition to the 48-h time point (see Fig. 2, lane 2), the SAP expression was also analyzed after 6, 12,
and 24 h. Also, at these earlier time points SAP expression could
not be detected. In addition, stimulation of DC precursors on day 4
with anti-CD40 mAbs did not alter the expression pattern of SLAM
isoforms or SAP in these mature DC (Fig. 2, lane 3).
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enhanced SLAM expression on mature DC
Final DC maturation was induced by a cytokine mixture composed of
GM-CSF, IL-4, TNF-, and PGE2. In contrast to
the observation by Jonuleit et al. (23), in our cell
culture system one proinflammatory cytokine, TNF- or IL-1, was
sufficient to generate phenotypically mature DC. In fact, DC matured in
the presence of TNF- only, without the addition of IL-1,
expressed high levels of CD83. In addition, these mature DC were also
SLAM positive.
Further analyses demonstrated that the addition of IL-1 to the
standard cytokine mixture composed of GM-CSF, IL-4, TNF-, and
PGE2 significantly enhanced the expression of
SLAM (Fig. 3). At an IL-1
concentration of 1 ng/ml, the SLAM expression was 
50% enhanced.
Decreasing IL-1 concentrations resulted in a lower SLAM expression,
whereas higher concentrations had no additional effects (data not
shown). In contrast, the expression levels of CD83 and CD25 were only
slightly affected by the addition of IL-1 (Fig. 3).
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effects in more detail, increasing
concentrations of an IL-1-neutralizing Ab or the recombinant human
IL-1RA were added to the cell cultures shortly before the induction of
the final DC maturation. As shown in Fig. 4, administration of IL-1RA results in a
clear reduction of SLAM surface expression. Similar results were
obtained with IL-1-neutralizing Abs (data not shown). These data
clearly demonstrate that IL-1 plays a major role in the induction of
SLAM surface expression on maturing DC.
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The functional consequences of SLAM engagement were analyzed by studying the effects of SLAM on the cell surface phenotype as well as the T cell stimulatory properties of DC on T cells. Agonistic anti-SLAM mAbs, or anti-CD40 mAbs, or the combination of both were added concurrently to the maturation mixture during the final DC maturation. Stimulation with anti-SLAM mAbs or anti-CD40 mAbs alone did not increase the basic level expression of the adhesion molecule ICAM-1 (CD54) and was comparable to the mock and IgG control (15% of cells were positive). Interestingly, the expression of ICAM-1 was clearly increased by the costimulation via SLAM and CD40 (30% of cells were positive). In contrast, the CD80 expression was only enhanced by anti-CD40 (from 14 to 24%) when compared with mock-treated cells. The combination of both anti-SLAM and anti-CD40 mAbs had no additional effect. Finally, the CD83 expression was not affected by CD40 and/or SLAM engagement. Furthermore, microscopic inspections revealed that in the presence of anti-SLAM and anti-CD40 mAbs DC gained the capacity to form large DC clusters (data not shown). DC that were only incubated with anti-CD40 mAbs also formed cell aggregates but these aggregates were considerably smaller than those generated in the presence of anti-CD40 and anti-SLAM mAbs. Anti-SLAM or mock treatment did not lead to the formation of cell clusters. These data suggest that the up-regulation of the ICAM-1 expression may increase the capacity of DC to form membrane-membrane interactions.
DC matured in the presence of IL-1 show an increased stimulation
of allogeneic T cell and peptide-specific CTL
The most distinctive functional characteristic of DC is their
potent capacity to stimulate T cells. Therefore, we studied whether or
not IL-1 affects the ability of DC to induce
CD4+ T cell proliferation in a primary allogeneic
MLR. As depicted in Fig. 5A,
addition of IL-1 to the maturation mixture increased the stimulatory
capacity of these DC. Interestingly, this increase could be inhibited
by the administration of IL-1RA or an inhibitory anti-IL-1 Ab. No
difference was observed when CD8+ T cells were
analyzed (data not shown).
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, primary allogeneic
cord-blood MLR analyses were performed. As shown in Fig. 5
B,
addition of IL-1 strongly increased the capacity of these DC to
stimulate naive T cells. In addition, when these T cells were counted
after the cocultivation with differentially matured DC, it became clear
that IL-1-matured DC increased the T cell number far better than cells
that were matured without IL-1 (Fig. 5C). Finally, the
effect on influenza matrix peptide M1-specific CTL was analyzed using
the ELISPOT assay. As demonstrated in Fig. 5D, in the
presence of IL-1 the DC showed an increased capacity to stimulate
influenza matrix peptide-specific memory cells. In conclusion,
it could be speculated that the up-regulation of SLAM by IL-1 leads
to an increased DC-induced T cell response. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Qualitative RT-PCR analyses confirmed these data and showed that only
mature DC express the membrane and the soluble isoform of SLAM. Both of
these isoforms have been shown to be agonistic (12).
Previous studies have demonstrated that CD83-specific mRNA was already
present in immature DC on day 5 (29, 30) as opposed to the
SLAM-specific mRNA which was not present in those DC precursors
(Fig. 2).
Interestingly, SLAM expression was clearly increased upon addition of
IL-1. The proinflammatory cytokine IL-1 is, like TNF-, an
important cytokine for the final maturation of DC. The present study
shows that the maturation effect of IL-1 on DC is reflected by the
enhancement of SLAM expression and that the SLAM expression is
specifically regulated in DC.
It is interesting to note that it has been known for some time, from
studies using DC isolated from murine tissue, that IL-1 has a distinct
effect on maturing DC. Koide et al. (31) reported that
IL-1 enhances the clustering and T cell stimulatory capacity of spleen
DC. Heufler et al. (32) found that IL-1 enhances the
stimulatory capacity of murine Langerhans cells matured in the presence
of GM-CSF. Later, Romani et al. (27) reported that IL-1
also enhanced the stimulatory capacity of DC generated from adherent
PBMC using GM-CSF and IL-4. Our finding that IL-1 induces
SLAM on maturing DC appears to provide the first mechanistic
explanation of these earlier findings.
The RT-PCR analyses also revealed that SAP, which binds in T cells to the intracellular domain of SLAM and regulates the recruitment of the phosphatases Src homology 2 domain-containing tyrosine phosphatase in T cells (15), is missing in DC. This suggests that in DC the SLAM-dependent signaling pathways differs from those in T cells. Nevertheless, the precise SLAM-dependent signaling events in DC still need to be elaborated. Interestingly, also B cells do not express SAP (Ref. 33 , and data not shown), indicating that APCs may have a different SLAM-dependent signaling cascade.
We found that some biological effects of SLAM ligation occur in concert with CD40 stimulation. Under these experimental conditions, SLAM enhanced the expression of ICAM-1 and concurrently the adhesion properties of DC.
This study outlines some potential key functions for SLAM on DC. First, SLAM is expressed on mature DC representing a new marker for mature DC and, second, SLAM may be responsible for the enhanced T cell stimulation. Since SLAM is expressed on both DC and T cells and has biological effects on both cell types, it could be envisaged that SLAM not only plays an essential role during the maturation of DC but additionally also in the T cell activation during the DC-T cell interaction in vivo.
Interestingly, SLAM has recently been identified as a measles virus receptor (16). It has previously been shown that measles virus can infect DC and thereby heavily interfere with the biology of DC. This includes the suppression of cell-mediated immunity by interfering with survival and function of the infected DC, leading to immunosuppression (34, 35, 36). Also, the reduced capacity to produce crucial cytokines such as IL-12 has been reported (36). Measles virus is still a major killer of children and the severe immunosuppression induced by this virus increases the risk of secondary infections in these patients and consequently leading to the high mortality. The Edmonston strain of measles virus, and the derived vaccine strains from it, use CD46 as cellular receptor (37). This molecule is expressed on all nucleated cells; nevertheless, most clinical isolates cannot use this receptor (38). SLAM on the other hand can be used as a receptor by measles viruses, including the Edmonston strain (16). The selective expression of SLAM on T and B cells and as we show now in this paper also on DC is consistent with their susceptibility to clinical isolates of measles virus. Therefore, DC probably represent a reservoir for measles virus infection and serve as a vector to transport the virus to the lymph nodes where it encounters and infects lymphoid cells. Since measles virus can infect DC and subsequently cause immunosuppression, the inhibition of the interaction between SLAM on DC and the virus might be an interesting way to protect the infected individuals.
In summary, our findings that SLAM is expressed on mature DC may not only help to further understand the cross-talk between DC and T cells but also to gain further insights into the interaction of DC and measles virus.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Alexander Steinkasserer, Department of Dermatology, University of Erlangen-Nürberg, Hartmannstrasse 4, D-91052,Erlangen, Germany. E-mail address: steinkasserer{at}derma.med.uni-erlangen.de
3 Abbreviations used in this paper: DC, dendritic cell; SLAM, signaling lymphocytic activation molecule; SAP, SLAM-associated protein; IL-1RA, IL-1R antagonist.
Received for publication December 26, 2000. Accepted for publication June 4, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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