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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-02-0438.
IMMUNOBIOLOGY
From the Division of Immunology of the Netherlands
Cancer Institute, Amsterdam, The Netherlands; and Schering
Plough Laboratory for Immunological Research, Dardilly,
France.
Human plasmacytoid dendritic cells (pDCs), also called type 2 dendritic cell precursors or natural interferon (IFN)-producing cells,
represent a cell type with distinctive phenotypic and functional features. They are present in the thymus and probably share a common
precursor with T and natural killer (NK) cells. In an effort to
identify genes that control pDC development we searched for genes of
which the expression is restricted to human pDC using a cDNA
subtraction technique with activated monocyte-derived DCs (Mo-DCs) as
competitor. We identified the transcription factor Spi-B to be
expressed in pDCs but not in Mo-DCs. Spi-B expression in pDCs was
maintained on in vitro maturation of pDCs. Spi-B was expressed in
early CD34+CD38 Dendritic cells (DCs) are specialized
antigen-presenting cells that both initiate primary specific immune
responses and delete potentially autoreactive T cells.1
There are different subsets of DCs with distinct cell surface
phenotypes, function, and anatomic localization.2,3 A
recently identified member of the DC lineage is the plasmacytoid DC
(pDC),4 also referred to as a type 2 DC
precursor5 (pre-DC2) or natural interferon
(IFN)-producing cell.6 These cells have been found in the
peripheral blood of adults and neonates7,8 and in the
T-cell areas of tonsils.4 Interestingly pDCs have the
capacity to produce high levels of type I IFNs that block viral
replication.6,9 Moreover, pDCs express a distinct pattern
of Toll-like receptors suggesting that they might have developed
through different evolutionary pathways to recognize different
microbial antigens.10 On activation with CD40L or with
virus, the pDCs differentiate into mature DCs, which can effectively
stimulate T cells. Depending on the way the pDCs are activated, the
mature DC2s induce T cells, producing distinct sets of cytokines:
interleukin 4 (IL-4) and IL-5 after activation of the pDCs with IL-3
and CD40L11 or IL-10 and IFN- Recent evidence strongly suggests that pDCs are of lymphoid origin.
pDCs lack myeloid-related markers CD13 and CD334,14 and express pre-T-cell receptor
(pT A number of transcription factors involved in lymphoid-lineage
specification in progenitor cells have been identified. GATA-3 and Pax5
are essential for T- and B-cell development,
respectively.20,21 Notch1 is required for T-cell
development and inhibits B-cell development and therefore determines
T/B-cell diversification22 and the HLH factor Id2 is
compulsory for development of natural killer (NK) cells.23
bHLH factors are involved in pDC development17 but are
also required for T- and B-cell development (for a review, see Eben
Massari and Murre24), raising the question which
transcription factor(s) might control the diversification of pDCs on
one hand and T, B, and NK cells on the other hand. To this end we
searched for genes that are specifically transcribed in pDCs. One of
the genes identified encodes the transcription factor Spi-B. We show here that forced expression of Spi-B in hematopoietic precursors impairs development of T, B, and NK cells and stimulates development of pDCs.
Reagents and mAbs
Generation of DCs from monocytes in vitro
Purification of plasmacytoid cells and generation of DC2s from
the CD4+CD1c Purification of blood cells and generation of CD34-derived DCs CD34-derived DCs were obtained after 6 and 12 days of culture of CD34+ progenitor cells in the presence of tumor necrosis factor (TNF-) and GM-CSF.26 DCs were activated by
CD40L-transfected cells. B lymphocytes were obtained from CD4-depleted
human tonsils. B cells were activated by CD40 activation using L cells
expressing CD40L. Blood mononuclear cells were obtained from human
peripheral blood by Ficoll-Hypaque centrifugation. T lymphocytes were
purified from peripheral blood mononuclear cells (PBMCs) by negative
depletion27 and activated by CD28-CD3. Granulocytes were
isolated by Lympholyte-poly centrifugation (Cedarlane
Laboratories, Hornby, ON, Canada) and activated by phorbol myristate
acetate (PMA; Sigma Chemical, St Louis, MO) and
ionomycin (Calbiochem, San Diego, CA) for 3 hours.
Subtractive hybridization The subtractive hybridization procedure was performed using the polymerase chain reaction (PCR)-select cDNA subtraction kit (Clontech, Palo Alto, CA), as per the manufacturer's protocols. Poly-A+ RNAs, selected as described by Mueller et al27 from pDCs and DC2s, were used as tester, and activated DC1 Poly-A+ RNAs as driver. To clone subtracted pDC cDNA, 10 PCRs (nested) were pooled and resolved on 2% low-melting agarose gel; 12 gel slices in the 0.3- to 1.3-kb size range were cut out and cloned with pCRII TOPO TA Cloning (Invitrogen, San Diego, CA). The inserts were sequenced by automatic sequencing. Comparisons against GenBank and dbest databases as well as protein homology prediction were obtained from the National Center for Biotechnology Information (NCBI) blast server (http://ncbi.nlm.nih.gov/BLAST/). The cloned product perfectly matched with the human Spi-B cDNA sequence (accession no. X66079).RT-PCR assays Reversed transcriptase (RT)-PCR assays were performed on RNA samples from purified T cells, granulocytes, PBMCs, tonsillar B cells, and day 12-harvested CD34+-derived DCs, before and after specific activation and CD34+ precursor cells isolated from fetal liver or thymus. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was performed on reverse-transcribed RNA from the different populations. GAPDH primers were 5'-ACCATGCTCGCCCTGGA (upstream) and 5'-GGCTAGCGAAGTTCTCC (downstream). In some experiments hypoxanthine phosphoribosyltransferase (HPRT) was used as a housekeeping gene. The sequences of the HPRT primers were 5'-TATGGACAGGACTGAACGTCTTGC (upstream) and 5'-GACACAAACATGATTCAAATCCCTGA (downstream). The sequences of the Spi-B primers were 5'-GGAGTGCTGCCCTGCCATAA (upstream) and 5'-CCCCCACCCCAGATGAGATT (downstream).Western blot analysis Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed on total cell lysates, and nuclear extracts obtained from 12 × 106 cells were subjected to 12% SDS-PAGE followed by electrotransfer onto nitrocellulose. Western blotting was performed as described.28 The membrane (polyvinylidene fluoride [PVDF]) was probed with an affinity-purified polyclonal antibody (kindly provided by Dr Françoise Moreau-Gachelin, Institut National de la Santé et de la Recherche Médicale, Institut Curie, Paris, France). Preimmune serum and anti-Spi-B were added at a 1:200 dilution in triethanolamine-buffered saline (TBS) containing 1% casein for 1 hour at room temperature. Immunoreactive bands were visualized by using secondary horseradish peroxidase (HRP)-conjugated antibodies (Santa Cruz Biotechnology, Santa Cruz, CA) and enhanced chemiluminescence (ECL; Boehringer Mannheim, Mannheim, Germany).Retroviral transductions Full-length human Spi-B and the natural splice variant lacking the DNA-binding domain ( Spi-B, kindly provided by Dr Françoise Moreau-Gachelin)29 cDNA was ligated into the multiple
cloning site of retroviral vector LZRS upstream of an internal
ribosomal entry site and enhanced green fluorescent protein (GFP) as
described previously.18,19 Control viruses were
LZRS-IRES-GFP. For some experiments we used as control virus LZRS-IRES
with, downstream placed, a deleted, signaling-incompetent mutant of the
nerve growth factor receptor (NGFR), kindly provided by Dr
C. Bordignon.30 Helper virus-free recombinant
retroviruses (titer 106/mL, as determined by transduction
of mouse 3T3 fibroblast cells) were produced after transfection of the
retroviral constructs into the 293T-based Phoenix ( NX-A) amphotropic
packaging cell line and selection on the selectable marker
puromycin.31 Transduction of
CD34+CD38 fetal liver or
CD34+CD1a postnatal thymocyte cells was
performed as described previously.32,33 Briefly, the
progenitor cells were cultured overnight in the presence of 20 ng/mL
IL-7 (R & D Systems) and 10 ng/mL SCF (R & D Systems) followed by
incubation for 7 to 8 hours or overnight with virus supernatant in
plates coated with fibronectin (30 µg/mL; Takara Biomedicals, Otsu,
Shiga, Japan).
Isolation of CD34+ cells from fetal liver and postnatal thymus The use of fetal liver and postnatal thymus tissue was approved by the Medical Ethical Committee of the Netherlands Cancer Institute and was contingent on informed consent. Human fetal tissues were obtained from elective abortions. Gestational age was determined by ultrasonic measurement of the diameter of the skull and ranged from 14 to 20 weeks. Human fetal liver cells were isolated by gentle disruption of the tissue by mechanical means, followed by density gradient centrifugation over Ficoll-Hypaque (Lymphoprep; Nycomed Pharma, Oslo, Norway). Thymus was obtained from surgical specimens removed from children undergoing open heart surgery. Single-cell suspensions were made from postnatal thymus by mincing tissues and pressing them through a stainless steel mesh. Large aggregates were removed and the cells were washed once before separating subpopulations. The CD34+ cells were isolated from these samples by immunomagnetic cell sorting, using a CD34 separation kit (varioMACS, Miltenyi Biotec). The CD34+ fetal liver cells were stained with anti-CD34 and anti-CD38 mAbs and further purified into CD34+CD38 cells by sorting with a FACStar
plus (Becton Dickinson, San Jose, CA). The purity of the
CD34+CD38 cells used in this study was more
than 99%. The CD34+ thymocytes were stained with
anti-CD34 and anti-CD1a and separated into
CD34+CD1a and
CD34+CD1a+ populations by cell sorting.
Differentiation assays Development of CD34+ cells into pDCs was determined following coculture with the mouse stromal cell line S17 as described previously.17 The hybrid murine/human fetal thymic organ culture has been described previously.34 To monitor NK-cell development in a fetal thymic organ culture (FTOC), 10 ng/mL IL-15 was added at the onset of the culture. The medium containing IL-15 was changed every week.To follow differentiation of T cells and pDCs in vivo we used an
immunodeficient mouse strain transplanted with human fetal thymus
fragments. RAG-2 The development of pDCs and B cells was assayed in a coculture of CD34+ progenitors with the murine marrow cell line MS-5 (kindly provided by Dr J. Plum, University of Ghent, Ghent, Belgium) in Iscove medium (Life Technologies) with 8% fetal calf serum. Statistical analysis To determine whether Spi-B significantly stimulates the development of pDCs from CD34+ progenitor cells, a paired 2-tailed Student t test was performed using Microsoft Excel 98.Apoptosis assay Apoptosis induced by Spi-B was measured in fluorescence-activated cell sorted (FACS) CD34+CD1 and
CD34+CD1+ postnatal thymocytes. Transduced
cells were cultured at 200 000 cells/96-well plate in 200 µL Yssel
medium supplemented with SCF and IL-7 (20 ng/mL each). At day
7 percentages of apoptotic and dead cells were determined by staining
with annexin V-PE (Becton Dickinson, Palo Alto, CA) and 7-amino-actino
mycin D (7-AAD; Becton Dickinson).
Identification of Spi-B in pDCs We performed a PCR-based subtraction technique on pDCs with monocyte-derived DC (DC1) as competitor. The subtractive hybridization technique was applied as described elsewhere.27 A mixture of freshly isolated pDC and pDC activated by IL-3 and CD40L for 24 hours (5 × 106 cells) was used as a tester, and 108 CD40-activated MoDC were used as competitor (driver). cDNA tester was cut with RsaI; the adapters were ligated and amplified after hybridization in the presence of driver. This technique combines normalization and subtraction in a single procedure. Thus, the resulting PCR products are restriction fragments of pDC cDNA, which are absent, or at least rare, in DC1 cells. pDC cDNA fragments were cloned and sequenced, and 30% of these clones contained unknown sequences.Of interest, we found 8 clones encoding the transcription factor
Spi-B. This factor belongs to the Ets family with a relatively high
degree of homology with PU.1 and was detected in lymphoid cells but in
contrast to PU.1, not in monocytes, granulocytes, or myeloid cell
lines.36 Spi-B transcripts have been shown to be present
in B and in developing T cells but not in most mature T
cells.36-38 To verify the restricted expression of Spi-B,
RT-PCR analysis was first performed on pDC and Mo-DC cDNAs (Figure
1A). pDCs (line 1) but not Mo-DCs (lines
7-9) expressed Spi-B mRNA. Importantly, Spi-B mRNA is maintained in
pDCs even after activation (lines 2-5). In addition, monocytes (line
6), peripheral blood T cells, and granulocytes did not express Spi-B.
As expected, high levels of Spi-B mRNA were found in resting and
activated B cells. Spi-B is also expressed in
CD34+CD38
To determine whether pDCs express Spi-B protein, Western blot analyses
were performed on whole cell lysates and nuclear extracts from pDCs,
Mo-DCs, and mature B cells as positive control (Figure 2). Comparable levels of the 46-kDa Spi-B
protein were detected, using a polyclonal antiserum raised against the
160 N-terminal amino acids of Spi-B,28 in whole cell
lysates from pDCs, mature tonsillar B cells, and nuclear extracts from
pDCs and mature tonsillar B cells. No Spi-B protein was precipitated
with the preimmune serum. As expected, the Jurkat T-cell line did not
express Spi-B protein (data not shown).
Effects of Spi-B on development of pDCs To investigate the function of Spi-B, we transduced hematopoietic CD34+CD38 fetal liver stem cells with a
retroviral vector harboring Spi-B upstream of IRES-GFP
DNA19 and tested the transduced cells in various
differentiation assays for pDC, T-, B-, and NK-cell development. Stem
cells transduced with Spi-B-GFP, with Spi-B or control GFP were incubated with the murine stromal cell line S17.17
Following 5 days of incubation the phenotypes of the
Spi-B-GFP+, Spi-B-GFP, and control
GFP+ cells were analyzed (Figure
3A). In this period of incubation, the
total numbers of cells do not increase and therefore differences in the
percentages of various cell populations reflect those in the absolute
numbers of cells. Whereas the Spi-B-GFP-transduced and the
control-transduced cells developed into pDCs in a manner comparable to
untransduced cells, we consistently observed that more pDCs are present
in the Spi-B-GFP+ population that developed from
CD34+CD38 fetal liver cells. A similar weak
stimulation of pDC development was seen on coculture of
Spi-B-transduced CD34+CD1a thymocytes with
S17 cells (Figure 3B).
Statistical analysis revealed that this difference in percentages (and
thus numbers) of pDCs between Spi-B-transduced samples as compared
with control- and
Inhibition of T- and NK-cell development by Spi-B Because Spi-B stimulated pDC development in the S17 assay, we investigated the effects of overexpression of Spi-B on development of other lymphoid lineages. CD34+CD38 fetal
liver cells were transduced with Spi-B or GFP control vector and
incubated in an FTOC. After incubation for 3 to 4 weeks, we analyzed
the phenotypes of the GFP+ cells in both cultures. T-cell
differentiation was inhibited at an early stage because in the
Spi-B/GFP gate only a few CD4+CD8+
double-positive (DP) cells could be detected when analyzed
after 3 weeks (Figure 4A). Moreover, the
number of the Spi-B-GFP+ cells generated per 1000 transduced CD34+CD38 cells was strongly
reduced compared with that of controls (Figure 4B). Analysis of the
FTOC incubated for 4 weeks revealed the presence of close to normal
proportions of cells expressing CD3, CD4, or CD8 but the numbers of
cells generated per 1000 input cells remained strongly reduced compared
with the control (Figure 4B). Development of NK cells was also strongly
inhibited (Figure 4).
To better reveal the effect of Spi-B on development of NK cells, we
added IL-15 to the FTOC, which stimulates NK-cell development in an
FTOC.40 Figure 5A confirms
that Spi-B-transduced CD34+ cells have a strongly
diminished capacity not only to develop into T but also to NK cells.
The absolute numbers of NK cells were also strongly reduced by Spi-B
(Figure 5B). Although not shown, ectopic expression of Spi-B also
inhibited NK-cell development of
CD34+CD38
Spi-B influences T-cell and pDC development in vivo Our data suggest that Spi-B expression in precursor cells within the thymus affects the lineage decision of CD34+ precursors into T cells or pDCs. To confirm this point, we examined whether Spi-B affects T/pDC diversification in a system where differentiation of both cell types could be followed simultaneously. In the in vitro FTOC system we do not observe appearance of pDCs. Therefore, we used a human immunodeficient mouse model in which we can monitor development of both pDCs and T cells.41 In this model gene-marked progenitor cells are injected into a human thymus grafted subcutaneously in RAG2/ c/ double-deficient
mice. Such mice lack T, B, and NK cells35 and are
therefore excellent recipients of human fetal thymus and liver (as
sources of stem cells) grafts. Like the thymus in the classical human
severe combined immunodeficient mouse, in which the thymus is grafted
under the kidney capsule,42 the subcutaneously placed
human thymus in the
RAG2/c/ mouse
has a normal architecture and contains normal proportions of all
thymocyte subsets.41 The thymus is palpable and therefore easily accessible for intrathymic injection without the need for surgery.41 We transduced
CD34+CD38 fetal liver stem cells with
Spi-B-GFP and with a control virus harboring a second marker, a
signaling-incompetent mutant of the NGFR with a deletion in the
cytoplasmic domain (NGFR30) and injected a mixture of
these transduced cells into the grafted human thymus. The use of 2 different markers, one for the Spi-B-modified and one for the control,
was necessary because a faithful comparison of development of modified
with control transduced cells can only be made when injected in the
same thymus. The thymic transplants of 2 transplanted mice can be
sufficiently different to make a comparison between these 2 samples
unreliable when injected into 2 different thymi. The transduction
efficiencies of the CD34+CD38 fetal liver
cells with Spi-B-GFP and control-NGFR in 3 different experiments
were comparable (7% ± 2%). Because from both samples the same
number of cells were injected, the input number of Spi-B and control
transduced cells were the same. Two weeks later we harvested the thymus
of each animal and compared the phenotypes of the Spi-B-transduced
(GFP+) and the control-transduced cells
(NGFR+; Figure 6). The
percentages of 2 transduced cell populations harvested from the thymi
were strikingly different because 0.7% of the thymocytes expressed GFP
and 5.7% NGFR, indicating a strong effect of Spi-B on the expansion
of the cells in this setting. The percentage of total
CD4+CD123+ cells that should include all pDCs
in the NGFR+ samples was 2%, but it needs to be noted
that almost no CD123high cells were present in these
samples. The percentage of CD123+CD4+ in the
Spi-B-transduced samples was significantly higher (8%) than in the
NGFR+ samples. The CD123+CD4+
cells in the Spi-B samples also expressed CD45RA. Part of these cells
also expressed BDCA2. This was not unexpected because in a normal
thymus the percentage of BDCA2+ is around 50% to 70% of
the percentage of all CD123+ cells (including
CD123low cells). Our pair of fluorogen-labeled antibodies
against BDCA2 and NGFR did not permit a simultaneous staining of
BDCA2+ cells in the NGFR-control samples, but because
the percentage of CD123+CD4+ cells in the
control is much lower than in the Spi-B-transduced sample we think it
is fair to conclude that ectopic Spi-B expression in
CD34+CD38 cells results in a higher
proportion of pDCs in vivo, which is consistent with the in vitro data.
Importantly, as was also observed in the in vitro FTOC assay, the
proportion of CD4+CD8+ T-cell lineage cells in
the Spi-B+ samples is lower than in the control
NGFR-transduced cells. This T cell-inhibiting effect of Spi-B is
more dramatic if one considers the much lower expansion of the
Spi-B-transduced cell samples.
Ectopic expression of Spi-B in early T-cell precursors increases apoptosis The observation that pDC development is modestly stimulated, whereas that of T cells is inhibited, together with the finding that DP T cells appear at later time points in the FTOC, may be explained by assuming that Spi-B inhibits proliferation or survival (or both) of T-cell precursors. To examine this possibility, we transduced CD34+CD1a and
CD34+CD1a+ cells with Spi-B or GFP and cultured
those cells for 7 days with IL-7 and SCF. The transduction efficiencies
as measured after 2 days were comparable. At 7 days, however, the
percentages of the Spi-B-transduced cells were only half of the
control (Figure 7). This suggested
already a reduced survival of the pre-T cells. Inspection of the
annexin V versus 7-AAD expression revealed that the Spi-B-transduced
cells contain many more annexinV+7-AAD
apoptotic cells than in the control. This effect was most striking in
the CD34+CD1a population although the same
pattern could also be observed in the
CD34+CD1a+ cells (Figure 7). These findings
strongly suggest that Spi-B inhibits T-cell development by induction of
apoptosis in T-cell precursors rather than inhibiting the
differentiation itself. The effect of Spi-B is specific because it does
not induce apoptosis in pDCs. Furthermore, ectopic Spi-B expression in
293T human embryonic kidney cells did not induce apoptosis in the cells
(supplemental figure on the Blood website; see the
Supplemental Figure link at the top of the online article).
Spi-B inhibits B-cell development Having established that Spi-B expression affects pDC versus T/NK-cell development, we examined whether Spi-B expression affects B-cell development. We transduced CD34+ fetal liver cells with Spi-B/GFP and control-GFP and cultured these cell samples with the stromal cell line MS-5. The cells were cocultured on the murine marrow line MS-5 for 2 weeks and analyzed for their expression of the B-cell markers CD10 and CD19 at days 7 and 14. Ectopic expression of Spi-B gives a strong block in the development of B cells. At 7 days the percentage of CD10+CD19+ is only 6% for the Spi-B-transduced population compared with 31% in the control cells (Figure 8). Moreover, when analyzed at 14 days the absolute number of CD10+CD19+ cells developing from CD34+ progenitor cells was strongly reduced by the forced expression of Spi-B (Figure 8). In the same assay at 5 days the percentage of pDCs was elevated similar to the results shown in Figure 3A (data not shown).
Evidence has been obtained that pDCs are lymphocyte related. Early
CD34+CD1a Inhibition of T-cell development by Spi-B is not absolute because
CD4+CD8+ cells are formed in vitro FTOCs and in
vivo in the thymus transplanted into
Rag2 It would also be of interest to investigate the presence of pDCs in
PU.1-deficient mice. The Ets domains of PU.1 and Spi-B display
70% homology and the factors bind to similar DNA sites, although the
transactivation domains are very different. The expression profiles of
these 2 transcription factors are widely different because Spi-B
expression appears to be limited to lymphoid cells, whereas PU.1 is
expressed in myeloid cells as well.36-38 PU.1 is essential
for B-cell development and important for T-cell
differentiation.46-48 Importantly, PU.1-deficient mice
lack myeloid CD8 The mechanism of interference of Spi-B with T-cell development is
unknown. T cell-specific target genes controlled by Spi-B have yet to
be found. However, the mechanism of inhibition of erythroid development
by PU.1 may provide a clue. Analysis of PU.1
We thank Dr F. Moreau-Gachelin for the polyclonal anti-Spi-B
antibody and the
Submitted February 8, 2002; accepted September 4, 2002.
Prepublished online as Blood First Edition Paper, September 19, 2002; DOI 10.1182/blood-2002-02-0438.
Supported by the Netherlands Organization for Science (NWO) grant 805.17.531 and by a grant from the Foundation Marcel Mérieux, Lyon, France (to N.B.-V.).
R.S. and M.-C. R. contributed equally to this work.
The online version of the article contains a data supplement.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hergen Spits, Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Meibergdreef 15.1105 AZ, Amsterdam, The Netherlands; e-mail: hergen.spits{at}amc.uva.nl.
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W. Dontje, R. Schotte, T. Cupedo, M. Nagasawa, F. Scheeren, R. Gimeno, H. Spits, and B. Blom Delta-like1-induced Notch1 signaling regulates the human plasmacytoid dendritic cell versus T-cell lineage decision through control of GATA-3 and Spi-B Blood, March 15, 2006; 107(6): 2446 - 2452. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
-like
transcripts,
), myeloid CD11c(+), and mature interdigitating dendritic cells.
J Clin Invest.
2001;107:835-844