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IMMUNOBIOLOGY
From the Thomas E. Starzl Transplantation Institute and
the Departments of Surgery, Molecular Genetics and Biochemistry, and
Dermatology, and the University of Pittsburgh Cancer Institute,
University of Pittsburgh Medical Center, PA.
Although it is known that dendritic cells (DCs) produce cytokines,
there is little information about how cytokine synthesis is regulated
during DC development. A range of cytokine mRNA/proteins was analyzed
in immature (CD86 Myeloid dendritic cells (DCs) are crucial
antigen-presenting cells (APCs) for primary T-cell responses. They
arise from bone marrow (BM) precursors that colonize peripheral tissues
through the blood or lymph.1,2 Tissue-resident immature
DCs are excellent at internalizing and processing antigen, but they
exhibit low ability to stimulate naive T cells. Exposure to allergens,
bacterial (lipopolysaccharide [LPS], CpG DNA motifs) or viral (dsRNA)
components, proinflammatory cytokines (interleukin-1 Although the capacity of DCs to produce an ample repertoire of
cytokines is documented in humans and rodents,3-27 there
is little information on how cytokine genes are expressed during DC
ontogeny.4 In this study, we analyzed a range of cytokine transcripts and their respective proteins in highly purified mouse BM-derived myeloid DCs (BM DCs) at different stages of cell
differentiation. Immature BM DCs expressed higher levels of IL-1 We also investigated the changes in the cytokine repertoire of BM
DCs terminally differentiated with LPS or after CD40 cross-linking. Both stimuli increased the levels of IL-6, IL-12p40, IL-15, and TNF- Experimental animals
Reagents
Generation of bone marrow dendritic cells The method for generating BM DCs was modified from that described originally by Inaba et al30 and has been described in detail.31 Briefly, BM cells were removed from femurs of B10 mice and depleted of erythrocytes by hypotonic lysis. Erythroid precursors, T and B lymphocytes, natural killer (NK) cells, granulocytes, and MHC-II+ cells were removed by complement depletion using a cocktail of monoclonal antibodies (mAbs) (anti-TER-119, anti-CD3 , anti-B220, anti-NK-1.1, anti-Gr1, and
anti-IAb; BD Pharmingen), followed by incubation with
rabbit complement (Cedarlane, Ontario, Canada). BM cells were cultured
in RPMI-1640 (Life Technologies, Grand Island, NY) in
75-cm2 flasks (5 × 106 cells/flask) with
10% heat-inactivated fetal calf serum (FCS; Life Technologies),
glutamine, nonessential amino acids, sodium pyruvate, HEPES, 2-ME, and
penicillin-streptomycin, supplemented with mrGM-CSF (1000 U/mL) and
rmIL-4 (1000 U/mL). Inclusion of mIL-4 reduced the development of
granulocytes (from approximately 35% to less than 5%) and
monocytes. Culture medium supplemented with cytokines was replaced at
day 3. At day 5, nonadherent cells were removed, and fresh medium with
cytokines was added. Two days later (day 7) 65% ± 15% of the new
population of nonadherent cells was CD11c+ DCs (CD11c is a
relatively restricted DC marker in the mouse; Figure
1A) with similar numbers of immature
(CD86 ) and mature (CD86+) DCs.
Flow cytometric analysis of cell surface phenotype BM-derived cells were blocked with normal goat serum and then incubated with biotin-conjugated anti-CD11c mAb (HL3; all mAbs were from BD Pharmingen), phycoerythrin (PE)-conjugated anti-CD86 mAb (GL1), and one of the following FITC-conjugated mAbs: anti-H2Kb (AF6-88.5), anti-IAb chain (25-9-17), anti-CD40 (3/23),
anti-CD80 (16-10A1), anti-CD11b (M1/70), or anti-CD54 (3E2). Incubation
with primary mAbs was followed by Cy-Chrome-streptavidin (BD
Pharmingen). For OX-40 ligand (L) labeling, BM cells were incubated
successively with (1) rat anti-OX-40L (RM134L) and biotin-conjugated
anti-CD11c mAbs; (2) FITC-conjugated F(ab')2 donkey
anti-rat immunoglobulin (Jackson ImmunoResearch Laboratory, West
Grove, PA) and Cy-Chrome-streptavidin; (3) irrelevant rat IgG to block
any residual rat immunoglobulin-binding sites of the FITC donkey
anti-rat immunoglobulins; and (4) PE-conjugated anti-CD86 mAb. Cells
were fixed in 2% paraformaldehyde and analyzed using an EPICS Elite
flow cytometer (Coulter, Hialeah, FL). Fluorochrome-conjugated species-
and isotype-matched irrelevant mAbs were used as negative controls.
Dendritic cell morphology and ultrastructure CD11c+CD86 and
CD11c+CD86+ flow-sorted DCs (purity, 92%-96%)
were used for cytospins or for transmission electron microscopy (TEM)
or scanning electron microscopy (SEM). For cytospins, DC were spun onto
glass slides using a Shandon cytocentrifuge (Cheshire, England)
(230g) and were stained with May-Grünwald-Giemsa. For TEM, DCs were fixed in 2.5% glutaraldehyde-1% osmium tetroxide, dehydrated, and embedded in Epon 812. Sections were stained with uranyl
acetate-lead citrate and were analyzed using a JEOL 1210 transmission
electron microscope (JEOL, Chicago, IL). For SEM, DCs attached to glass
coverslips pretreated with 0.1% poly-L-lysine were fixed with 2.5%
glutaraldehyde, dehydrated, coated with 20 nm evaporated carbon, and
analyzed in a JEOL 35 scanning electron microscope.
Endocytosis assay Day 7 BM DCs were purified by labeling with bead-conjugated anti-CD11c mAb (Miltenyi Biotec, Auburn, CA) followed by positive selection through paramagnetic columns (Miltenyi Biotec) (DC purity, 90%-93%). Immunobead-sorted DC were incubated with 5 µg/mL FITC-albumin or 0.1 mg/mL FITC-dextran, at 37°C or at 4°C for 1 hour. Uptake was stopped by 3 washes with ice-cold 0.1% sodium azide-1% FCS-phosphate-buffered saline (PBS). After staining with PE anti-CD86 mAb (30 minutes on ice), cells were fixed with 2% paraformaldehyde and analyzed by flow cytometry.RNase protection assay The procedure adopted for RNase protection assay (RPA) has been described.31 Briefly, RNA was isolated from 5 × 106 snap-frozen, flow-sorted DCs using a total RNA Isolation Kit (BD Pharmingen). RPA was performed using the RiboQuant Multi-Probe RPA System (BD Pharmingen). Four kits containing cDNAs encoding mouse IL-1 , IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7,
IL-9, IL-10, IL-11, IL-12p35, IL-12p40, IL-13, IL-15, IL-18, IFN-, IFN-, IFN- , TNF-, TGF-1, TGF-2, TGF-3, MIF, and the
housekeeping genes L32 and glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) were used as templates for the T7
polymerase-directed synthesis of 32P-UTP-labeled antisense
RNA probes. Hybridization (16 hours at 56°C) of 5 µg each target
mRNA with the antisense RNA probes sets was followed by RNase and
proteinase K treatment, phenol-chloroform extraction, and ammonium
acetate precipitation of protected RNA duplexes. In each RPA, the
corresponding antisense RNA probe set was included as molecular weight
standard. Mouse RNA and RNA degradation controls were included. Yeast
tRNA served as negative control. Samples were electrophoresed on
acrylamide-urea sequencing gels, and dried gels were exposed on x-ray
film at  80°C. Quantification of bands was performed by densitometry
followed by assessment using Image QuantNT software (Molecular
Dynamics, Sunnyvale, CA). The signals from specific mRNA were
normalized to signals from housekeeping genes (L32 and
GADPH) run on each lane to adjust for loading differences.
Intracellular cytokine staining BM DCs were treated with brefeldin A (10 µg/mL; 5 hours at 37°C), fixed in 4% paraformaldehyde, and permeabilized with 0.1% saponin-1% FCS-PBS. DCs were incubated with one of the following PE-coupled mAbs (all from BD Pharmingen): anti-mIL-4 (BVD4-1D11), anti-mIL-5 (TRFK5), anti-mIL-6 (MP5-2OF3), anti-mIL-10 (JES5-16E3), anti-mIL-12 p40/p70 (C15.6), anti-mTNF- (MP6-XT22), or
anti-mIFN- (XMG1.2). DCs were also incubated with either rat
anti-mIL-1 (MAB500; R&D), anti-mIL-1 (MAB401; R&D),
anti-mIL-12p70 mAbs (9A5; BD Pharmingen), or anti-mIFN- (RMMA-1;
PBL Biomedical Laboratories, New Brunswick, NJ); or rabbit anti-mIL-15
(H-114) or goat anti-mIL-18 (C-18, both from Santa Cruz Biotechnology)
polyclonal IgG. In a second step, cells were incubated with PE goat
F(ab')2 anti-rat IgG, PE goat F(ab')2
anti-rabbit IgG, or PE swine anti-goat IgG (Caltag Laboratories,
Burlingame, CA). After cytokine staining, DCs were labeled with FITC
anti-CD86 or FITC anti-CD11c mAbs, fixed in 2% paraformaldehyde, and
analyzed by flow cytometry.
Cytokines were detected in responder T cells after 3-day MLR
(stimulator-responder cell ratio, 1:10) as described.32
Briefly, T cells were restimulated with plate-bound anti-CD3 Cytokine quantitation IL-4, IL-10, and TGF-1 were quantified in 24-hour
supernatants of DC cultures using an ELISA kit (OptEIA; BD Pharmingen) according to the manufacturer's protocol.
Allostimulatory activity B10 BM DCs were flow-sorted into CD11c+CD86 or
CD11c+CD86+ DCs, -irradiated, and used as
stimulators in 72-hour primary MLR using nylon-wool column purified
allogeneic (C3H) splenic T cells or naive CD4+ T cells as
responders.32 Naive
CD4+CD62L+CD44low T cells were
purified by negative selection (purity 94% or greater) using T-cell
enrichment columns (R&D). As controls, allogeneic (B10) or syngeneic
(C3H) splenocytes were used as stimulators.
Statistical analysis Results are expressed as means ± 1 SD. Comparisons between different means were performed by analysis of variance and then by the Newman-Keuls test. Comparison between 2 means was performed by the Student t test. P < .05 was considered significant.
Stages of differentiation of bone marrow dendritic cells in vitro BM DCs generated in vitro with GM-CSF + IL-4 exhibited (day 7) a mixed population of CD86 and
CD86+CD11c+ DCs (Figure 1A). A third population
of nonadherent, CD11cCD86 cells was also
detected. CD11c+ DCs were negative for monocyte-macrophage
(CD14, F4/80), T-cell (CD3), B-cell (B220, CD19), NK-cell (NK1.1),
and granulocyte (Gr-1) markers. The lack of CD8 (expressed by
"lymphoid-related" DCs in the mouse) was consistent with the
myeloid lineage of CD11c+ DCs generated with GM-CSF + IL-4. As expected, CD86 DCs corresponded to immature APCs
(MHC-Ilo, MHC-IIlo, CD40/lo,
CD80lo, CD11bhi, CD54lo,
OX40L) that induced minimal proliferation of naive T
cells (Figure 1B,D) in a 72-hour MLR. Classification of
CD86 DCs as immature APCs was further confirmed by their
capacity to internalize exogenous FITC-dextran or FITC-albumin, a
function down-regulated at 0°C, or when DC expressed CD86 on the
surface (Figure 1C). By contrast, CD86+ DCs exhibited the
phenotype of mature DCs (MHC-Ihi, MHC-IIhi,
CD40+, CD80hi, CD11blo,
CD54hi, OX40L+), lacked endocytic capacity, and
triggered a potent allogeneic naive T-cell response (Figure
1).
To confirm that CD86
The proliferative capacity of FACS-sorted double-negative cells,
CD86 FACS-sorted CD86
Immature (CD86 or CD86+ DC (purity, approximately 95%)
were used for RNA extraction. CD86 DCs expressed higher
levels of IL-1, IL-1, TNF-, TGF-1, and MIF mRNA than
CD86+ DCs (Figure 4A-B). Both
DC subpopulations showed weak but similar signals for TGF-2 and
TGF-3. Production of IL-6 and IL-15 mRNA, and to a lesser extent,
the level of IFN- mRNA, increased during DC differentiation.
CD86+ DCs showed de novo expression of IL-12p35, IL-12p40,
and IL-18 mRNA (Figure 4A-B). We were unable to detect mRNA for IL-2,
IL-3, IL-4, IL-5, IL-7, IL-9, IL-10, IL-13, IFN-, and IFN-, even
after increasing the x-ray film exposure time (up to 4 days) or the amount of total RNA used in the hybridization (up to 6 µg).
In view of conflicting reports of the effect of IL-4 on synthesis of
IL-12 by DCs,16,33-37 we compared cytokine mRNA of
CD86 Immature dendritic cells exhibit a different pattern of cytokine protein synthesis than mature dendritic cells The pattern of cytokine expression during DC ontogeny (with the exception of TGF-1) was assessed by intracellular staining, followed by flow cytometry analysis. This methodology circumvented some
of the following obstacles related to the detection of cytokines in a
dynamic population of cells at different stages of differentiation: (1)
purified immature DCs differentiate rapidly into mature DCs; hence, the
ultimate cellular source of a secreted cytokine cannot be identified by
analysis of culture supernatants by ELISA; (2) some cytokines exhibit a
short half-life after being released into the medium; and (3) some of
the cytokines analyzed are consumed by DCs (ie, TNF-, IL-1, IL-4,
IL-12). The production of IL-1, IL-1, IL-15, and TNF- protein
by CD86 and CD86+ immunobead-sorted
CD11c+ DCs and the synthesis of IL-6, IL-12p40, IL-12p70,
IL-18, and IFN- protein almost exclusively by CD86+ DC
were confirmed by FACS (Figure 5A). In
agreement with the RPA results, expression of IL-4, IL-5, IL-10, and
IFN- was absent in DC by FACS analysis and confirmed by ELISA
(not shown).
Despite the TGF- Terminal maturation of dendritic cells by distinct stimuli regulates differentially the levels and pattern of cytokine mRNA and protein To analyze whether the pattern of cytokines produced by murine DCs was determined by the molecular pathway used for terminal differentiation, the levels of cytokine mRNA and protein were assessed in CD86+ DCs before and after activation by either a T-cell-independent (LPS) or a T-cell-dependent (CD40 ligation) pathway. Total RNA was extracted from CD11c+CD86+ FACS-sorted DCs incubated with either LPS (0.5 µg/mL) or IgM anti-CD40 (10 µg/mL), or irrelevant IgM (10 µg/mL). To avoid the exhaustion of cytokine production, as reported recently for human DCs,38 and based on our preliminary observations that the maximum expression of most cytokine mRNAs analyzed was within 6 and 16 hours of stimulation, the final experiments were carried out after 10 hours of LPS or anti-CD40 treatment. Terminal differentiation of CD86+ DCs induced by LPS or CD40 cross-linking was confirmed by increases in the surface levels of MHC-I and MHC-II, CD40, CD80, CD86, and in the cells' allogeneic T-cell stimulatory capacity (not shown).LPS up-regulated significantly the levels of IL-1
Unlike LPS, CD40 ligation of DCs induced more discrete changes in the
levels of cytokine mRNA. Only IL-6, IL-12p40, IL-15, and TNF- The level of intracellular IL-18 and IFN- IFN- Transcription of IL-12 genes in CD86+ dendritic cells is affected differentially by lipopolysaccharide and CD40 cross-linking DCs secrete IL-12p70, a heterodimeric cytokine composed of p35 and p40 chains, covalently linked and encoded by different genes. Secretion of IL-12p70 by DCs during the early stages of antigen presentation directs the differentiation of naive Th cells into Th1 lymphocytes. CD86+ DC express IL-12p40 mRNA and low levels of IL-12p35 mRNA (Figures 4A, 6A). Either LPS or anti-CD40 stimulation of DCs increased significantly the amount of IL-12p40 transcripts (Figure 6A-B) and intracellular IL-12p40 protein detected by FACS (Figure 7A). Interestingly, unlike CD40 ligation, LPS stimulation augmented IL-12p35 transcripts markedly, and the levels of IL-12p70 protein detected by FACS using a mAb specific for the p35/p40 heterodimer, a fact indicative of an increased synthesis of IL-12p35 protein (Figure 7A). Similar results were obtained with DCs generated in the absence of IL-4 (not shown).Mature dendritic cells exhibit a DC1/DC2 phenotype (Th1/Th2 driving capacity) maintained after CD40 cross-linking, but they shift toward DC1 after terminal differentiation with LPS The type of allogeneic Th response elicited by CD86+ DCs, before and after terminal differentiation with LPS or CD40 cross-linking, was studied by flow cytometry. FACS-sorted CD86+ (B10) DCs, either nonstimulated or after treatment with LPS, anti-CD40 IgM mAb or irrelevant IgM was used as a stimulator of (C3H) splenic T cells in 3d-MLR. Responder T cells were triple labeled with Cy-Cychrome anti-CD3, FITC anti-CD4, and PE
anti-mIFN- or anti-mIL-10 or anti-mIL-4 mAbs. Allogeneic DCs were
gated out of the mixed cell population from the MLR (C3H T cells and
B10 DC at a ratio of 10:1) according to their lack of CD3 expression. When CD86+ DCs or anti-CD40 treated-DCs were used as
stimulators, a substantial percentage of CD4+ splenic T
cells (approximately 11%-12%; Figure
8B,F) produced IFN-, and a lower
proportion synthesized Th2 cytokines (approximately 5%-6% and
approximately 2%-3% produced IL-4 or IL-10, respectively; Figure 8).
Similar results were obtained with control DCs incubated with
irrelevant IgM (not shown). By contrast, when DCs were differentiated with LPS, CD4+ splenic T cells produced exclusively IFN-
(Figure 8J).
IL-12 p70 (IL-12p35/IL-12p40), and not IL-23 (p19/IL-12p40), is mainly involved in Th1-driving capacity of lipopolysaccharide-treated dendritic cells IL-23 is a cytokine that combines the IL-12p40 subunit with p19.39 Like IL-12 p70, IL-23 induces proliferation and IFN- production by T cells.39 In the mouse, IL-23
induces exclusively the proliferation of memory T cells, whereas
IL-12p70 only affects naive T lymphocytes.39 Because it
was not possible to analyze expression of the recently defined IL-23p19
mRNA/protein, 2 alternative approaches were used to address the role of
IL-23 in the Th1-driving potential of CD86+ DCs in our
system. First, untreated control, anti-CD40-treated, or LPS-treated
CD86+ (B10) DCs were used as stimulators of (C3H) splenic T
cells in 3d-MLR in the presence of neutralizing anti-IL-12p35 mAbs (20 µg/mL) to establish a role for IL-12p70. Alternatively, neutralizing anti-IL-12p40 mAbs (20 µg/mL) were used to rule out a role for IL-23. In all cases, there was a substantial decrease in the number of
IFN-+ CD4+ T cells (Figure
9A). In a second approach, highly
purified allogeneic (C3H)
CD4+CD62L+CD44low naive splenic T
cells were used as responders in 3d-MLR. Control or anti-CD40-treated
CD86+ DCs induced a mixed Th1/Th2 response, whereas
LPS-treated CD86+ DCs generated predominantly Th1 cells
(Figure 9B). These results confirm that the Th1 shift caused by LPS was
caused mainly by the increased production of IL-12p35 by DCs.
Our results demonstrate that BM-derived myeloid DCs
transcribe different spectra of cytokines at distinct stages of
development. CD86 IL-15 shares with IL-2 the capacity to stimulate T-cell proliferation and induction of cytotoxic T lymphocyte and lymphokine-activated killer cells.43 Because IL-2 is not produced by DCs, the secretion of IL-15, whose mRNA/protein levels increased during DC maturation, may provide alternative cytokine costimulation for T cells.21 IL-15 is also chemotactic for T cells.44 Thus, secretion of IL-15 by mature DCs may serve to recruit T cells and, hence, facilitate the initial cell contact during antigen presentation. In line with the role of IL-15 in T-cell costimulation by DCs, the IL-15 mRNA/protein levels increased after terminal differentiation of mature DCs induced by LPS or CD40 cross-linking. Other bacterial products (Staphylococcus aureus Cowan I strain: SAC), and other members of the TNF family (such as TRANCE, TNF-related activation-induced cytokine) increase IL-15 levels in human and mouse DCs.11 IL-12 is a 70-kd heterodimeric cytokine composed of 2 covalently linked chains, p40 and p35, encoded by 2 separate genes regulated independently. Release of IL-12p70 by DCs is the key factor that drives the differentiation of naive T lymphocytes to Th1 cells (so-called DC1).12,15,28 The present work demonstrates that transcription of both IL-12 mRNAs occurs late during DC development, at the CD86+ stage. Similarly, the level of IL-12p40 mRNA is augmented in Langerhans cells or Langerhans cell lines during maturation in culture,14,45 and IL-12p70 secretion correlates with the maturation of splenic DCs.40 Our results show that CD40 ligation increased the level of IL-12p40
mRNA/protein in BM DCs but did not affect p35 mRNA/protein expression.
This indicates that CD40 ligation triggers activation signals for
IL-12p40 mRNA transcription, but not for IL-12p35. It is known that
CD40 cross-linking induces the up-regulation of IL-12p40 mRNA in
monocytic and B-cell lines and in human monocyte-derived DCs6,46 through activation of the transcription factor
NF- In contrast to CD40 cross-linking, LPS stimulation increased the
levels of IL-12p35 mRNA/protein in CD86+ DCs. The presence
of a small amount of IFN- Other cytokines involved in T-cell priming (IL-1- It is interesting that, after differentiation into
CD11c+CD86+ cells, mature BM-derived DCs
express IL-18 (IFN- There has been controversy as to whether DCs, like macrophages, are
able to produce IFN- We were unable to detect IFN- In conclusion, we have demonstrated that mouse BM DCs modulate their repertoire of cytokine mRNAs/proteins at different stages of development. Although CD40 ligation or LPS stimulation induced similar changes in phenotype and allostimulatory activity in mature myeloid DCs, these stimuli generated different cytokine patterns in DCs and induced distinct naive Th-cell-driving potential (Th1/Th2 vs Th1). Inflammatory cytokines (IFN-
We thank Mr Jan Urso and Ms Nancy Zurowski for skillful assistance with cell culture techniques, Dr Donna Stolz for assistance with electron microscopy, and Mr Cipriano Almonte and Dr Simon Watkins for image processing. We thank the Schering-Plough Research Institute for the gifts of cytokines.
Submitted December 7, 2000; accepted May 2, 2001.
Supported by National Institutes of Health grants DK 49745 and AI 41011 (A.W.T.) and DC Program Project grant CA 73743. A.E.M. is the recipient of an American Heart Association Scientist Development Grant, and A.T.L. is the recipient of a Dermatology Foundation Research Career Development Award.
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: Adrian E. Morelli, Department of Surgery, University of Pittsburgh Medical Center, W1540 Biomedical Science Tower, 200 Lothrop St, Pittsburgh, PA 15213; e-mail: morelli{at}imap.pitt.edu.
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  S. Alzabin, N. Bhardwaj, F. Kiefer, S. Sawasdikosol, and S. Burakoff Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation J. Immunol., May 15, 2009; 182(10): 6187 - 6194. [Abstract] [Full Text] [PDF]
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X. Li, T. Syrovets, S. Paskas, Y. Laumonnier, and T. Simmet Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction J. Immunol., July 15, 2008; 181(2): 1215 - 1223. [Abstract] [Full Text] [PDF]
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H. R. Turnquist, T. L. Sumpter, A. Tsung, A. F. Zahorchak, A. Nakao, G. J. Nau, F. Y. Liew, D. A. Geller, and A. W. Thomson IL-1{beta}-Driven ST2L Expression Promotes Maturation Resistance in Rapamycin-Conditioned Dendritic Cells J. Immunol., July 1, 2008; 181(1): 62 - 72. [Abstract] [Full Text] [PDF]
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W. H. Wheat, K. E. Pauken, R. V. Morris, and R. G. Titus Lutzomyia longipalpis Salivary Peptide Maxadilan Alters Murine Dendritic Cell Expression of CD80/86, CCR7, and Cytokine Secretion and Reprograms Dendritic Cell-Mediated Cytokine Release from Cultures Containing Allogeneic T Cells J. Immunol., June 15, 2008; 180(12): 8286 - 8298. [Abstract] [Full Text] [PDF]
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J. Jantsch, D. Chakravortty, N. Turza, A. T. Prechtel, B. Buchholz, R. G. Gerlach, M. Volke, J. Glasner, C. Warnecke, M. S. Wiesener, et al. Hypoxia and Hypoxia-Inducible Factor-1{alpha} Modulate Lipopolysaccharide-Induced Dendritic Cell Activation and Function J. Immunol., April 1, 2008; 180(7): 4697 - 4705. [Abstract] [Full Text] [PDF]
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 I. Ifergan, H. Kebir, M. Bernard, K. Wosik, A. Dodelet-Devillers, R. Cayrol, N. Arbour, and A. Prat The blood-brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells Brain, March 1, 2008; 131(3): 785 - 799. [Abstract] [Full Text] [PDF]
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G. Chen, G. Han, J. Wang, R. Wang, R. Xu, B. Shen, J. Qian, and Y. Li Essential roles of TGF-{beta} in anti-CD3 antibody therapy: reversal of diabetes in nonobese diabetic mice independent of Foxp3+CD4+ regulatory T cells J. Leukoc. Biol., February 1, 2008; 83(2): 280 - 287. [Abstract] [Full Text] [PDF]
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J. Hanig and M. B. Lutz Suppression of Mature Dendritic Cell Function by Regulatory T Cells In Vivo Is Abrogated by CD40 Licensing J. Immunol., February 1, 2008; 180(3): 1405 - 1413. [Abstract] [Full Text] [PDF]
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S. Yamazaki, A. J. Bonito, R. Spisek, M. Dhodapkar, K. Inaba, and R. M. Steinman Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors Blood, December 15, 2007; 110(13): 4293 - 4302. [Abstract] [Full Text] [PDF]
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H. R. Turnquist, G. Raimondi, A. F. Zahorchak, R. T. Fischer, Z. Wang, and A. W. Thomson Rapamycin-Conditioned Dendritic Cells Are Poor Stimulators of Allogeneic CD4+ T Cells, but Enrich for Antigen-Specific Foxp3+ T Regulatory Cells and Promote Organ Transplant Tolerance J. Immunol., June 1, 2007; 178(11): 7018 - 7031. [Abstract] [Full Text] [PDF]
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R. Gandhi, D. E. Anderson, and H. L. Weiner Cutting Edge: Immature Human Dendritic Cells Express Latency-Associated Peptide and Inhibit T Cell Activation in a TGF-beta-Dependent Manner J. Immunol., April 1, 2007; 178(7): 4017 - 4021. [Abstract] [Full Text] [PDF]
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F. Moore, S. Buonocore, E. Aksoy, N. Ouled-Haddou, S. Goriely, E. Lazarova, F. Paulart, C. Heirman, E. Vaeremans, K. Thielemans, et al. An Alternative Pathway of NF-{kappa}B Activation Results in Maturation and T Cell Priming Activity of Dendritic Cells Overexpressing a Mutated I{kappa}B{alpha} J. Immunol., February 1, 2007; 178(3): 1301 - 1311. [Abstract] [Full Text] [PDF]
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D. C. Webb, Y. Cai, K. I. Matthaei, and P. S. Foster Comparative Roles of IL-4, IL-13, and IL-4R{alpha} in Dendritic Cell Maturation and CD4+ Th2 Cell Function J. Immunol., January 1, 2007; 178(1): 219 - 227. [Abstract] [Full Text] [PDF]
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Y. Y. Lan, Z. Wang, G. Raimondi, W. Wu, B. L. Colvin, A. De Creus, and A. W. Thomson "Alternatively Activated" Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig J. Immunol., November 1, 2006; 177(9): 5868 - 5877. [Abstract] [Full Text] [PDF]
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M. J. Perone, S. Bertera, Z. S. Tawadrous, W. J. Shufesky, J. D. Piganelli, L. G. Baum, M. Trucco, and A. E. Morelli Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice J. Immunol., October 15, 2006; 177(8): 5278 - 5289. [Abstract] [Full Text] [PDF]
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 A. Grolleau-Julius, M. R. Garg, R. Mo, L. L. Stoolman, and R. L. Yung Effect of Aging on Bone Marrow-Derived Murine CD11c+CD4-CD8{alpha}- Dendritic Cell Function. J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2006; 61(10): 1039 - 1047. [Abstract] [Full Text] [PDF]
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Q. Wang, Y. Liu, J. Wang, G. Ding, W. Zhang, G. Chen, M. Zhang, S. Zheng, and X. Cao Induction of Allospecific Tolerance by Immature Dendritic Cells Genetically Modified to Express Soluble TNF Receptor J. Immunol., August 15, 2006; 177(4): 2175 - 2185. [Abstract] [Full Text] [PDF]
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M. J. Perone, A. T. Larregina, W. J. Shufesky, G. D. Papworth, M. L. G. Sullivan, A. F. Zahorchak, D. B. Stolz, L. G. Baum, S. C. Watkins, A. W. Thomson, et al. Transgenic galectin-1 induces maturation of dendritic cells that elicit contrasting responses in naive and activated T cells. J. Immunol., June 15, 2006; 176(12): 7207 - 7220. [Abstract] [Full Text] [PDF]
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Y. Peng, H. Shao, Y. Ke, P. Zhang, J. Xiang, H. J. Kaplan, and D. Sun In Vitro Activation of CD8 Interphotoreceptor Retinoid-Binding Protein-Specific T Cells Requires not only Antigenic Stimulation but also Exogenous Growth Factors. J. Immunol., April 15, 2006; 176(8): 5006 - 5014. [Abstract] [Full Text] [PDF]
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G. Raimondi, W. J. Shufesky, D. Tokita, A. E. Morelli, and A. W. Thomson Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells. J. Immunol., March 1, 2006; 176(5): 2808 - 2816. [Abstract] [Full Text] [PDF]
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A. E. Morelli, J. P. Rubin, G. Erdos, O. A. Tkacheva, A. R. Mathers, A. F. Zahorchak, A. W. Thomson, L. D. Falo Jr., and A. T. Larregina CD4+ T Cell Responses Elicited by Different Subsets of Human Skin Migratory Dendritic Cells J. Immunol., December 15, 2005; 175(12): 7905 - 7915. [Abstract] [Full Text] [PDF]
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 F. Ghiringhelli, P. E. Puig, S. Roux, A. Parcellier, E. Schmitt, E. Solary, G. Kroemer, F. Martin, B. Chauffert, and L. Zitvogel Tumor cells convert immature myeloid dendritic cells into TGF-{beta}-secreting cells inducing CD4+CD25+ regulatory T cell proliferation J. Exp. Med., October 3, 2005; 202(7): 919 - 929. [Abstract] [Full Text] [PDF]
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M. Feili-Hariri, D. H. Falkner, and P. A. Morel Polarization of naive T cells into Th1 or Th2 by distinct cytokine-driven murine dendritic cell populations: implications for immunotherapy J. Leukoc. Biol., September 1, 2005; 78(3): 656 - 664. [Abstract] [Full Text] [PDF]
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R. Ruckert, K. Brandt, A. Braun, H.-G. Hoymann, U. Herz, V. Budagian, H. Durkop, H. Renz, and S. Bulfone-Paus Blocking IL-15 Prevents the Induction of Allergen-Specific T Cells and Allergic Inflammation In Vivo J. Immunol., May 1, 2005; 174(9): 5507 - 5515. [Abstract] [Full Text] [PDF]
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I. Rochman, W. E. Paul, and S. Z. Ben-Sasson IL-6 Increases Primed Cell Expansion and Survival J. Immunol., April 15, 2005; 174(8): 4761 - 4767. [Abstract] [Full Text] [PDF]
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A. E. Morelli, A. T. Larregina, W. J. Shufesky, M. L. G. Sullivan, D. B. Stolz, G. D. Papworth, A. F. Zahorchak, A. J. Logar, Z. Wang, S. C. Watkins, et al. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells Blood, November 15, 2004; 104(10): 3257 - 3266. [Abstract] [Full Text] [PDF]
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 J. Li, T. Moran, E. Swanson, C. Julian, J. Harris, D. K. Bonen, M. Hedl, D. L. Nicolae, C. Abraham, and J. H. Cho Regulation of IL-8 and IL-1{beta} expression in Crohn's disease associated NOD2/CARD15 mutations Hum. Mol. Genet., August 15, 2004; 13(16): 1715 - 1725. [Abstract] [Full Text] [PDF]
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Z. Wang, A. Castellaneta, A. De Creus, W. J. Shufesky, A. E. Morelli, and A. W. Thomson Heart, but Not Skin, Allografts from Donors Lacking Flt3 Ligand Exhibit Markedly Prolonged Survival Time J. Immunol., May 15, 2004; 172(10): 5924 - 5930. [Abstract] [Full Text] [PDF]
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J. R. Ramirez-Pineda, A. Frohlich, C. Berberich, and H. Moll Dendritic Cells (DC) Activated by CpG DNA Ex Vivo Are Potent Inducers of Host Resistance to an Intracellular Pathogen That Is Independent of IL-12 Derived from the Immunizing DC J. Immunol., May 15, 2004; 172(10): 6281 - 6289. [Abstract] [Full Text] [PDF]
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G. Schiavoni, F. Mattei, P. Borghi, P. Sestili, M. Venditti, H. C. Morse III, F. Belardelli, and L. Gabriele ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells Blood, March 15, 2004; 103(6): 2221 - 2228. [Abstract] [Full Text] [PDF]
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B. L. Colvin, A. E. Morelli, A. J. Logar, A. H. Lau, and A. W. Thomson Comparative evaluation of CC chemokine-induced migration of murine CD8{alpha}+ and CD8{alpha}- dendritic cells and their in vivo trafficking J. Leukoc. Biol., February 1, 2004; 75(2): 275 - 285. [Abstract] [Full Text] [PDF]
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V. Paharkova-Vatchkova, R. Maldonado, and S. Kovats Estrogen Preferentially Promotes the Differentiation of CD11c+ CD11bintermediate Dendritic Cells from Bone Marrow Precursors J. Immunol., February 1, 2004; 172(3): 1426 - 1436. [Abstract] [Full Text] [PDF]
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A. T. Larregina, A. E. Morelli, O. Tkacheva, G. Erdos, C. Donahue, S. C. Watkins, A. W. Thomson, and L. D. Falo Jr Highly efficient expression of transgenic proteins by naked DNA-transfected dendritic cells through terminal differentiation Blood, February 1, 2004; 103(3): 811 - 819. [Abstract] [Full Text] [PDF]
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Z. Guo, M. Zhang, H. An, W. Chen, S. Liu, J. Guo, Y. Yu, and X. Cao Fas ligation induces IL-1{beta}-dependent maturation and IL-1{beta}-independent survival of dendritic cells: different roles of ERK and NF-{kappa}B signaling pathways Blood, December 15, 2003; 102(13): 4441 - 4447. [Abstract] [Full Text] [PDF]
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K. Brandt, S. Bulfone-Paus, D. C. Foster, and R. Ruckert Interleukin-21 inhibits dendritic cell activation and maturation Blood, December 1, 2003; 102(12): 4090 - 4098. [Abstract] [Full Text] [PDF]
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C. L. Doxsee, T. R. Riter, M. J. Reiter, S. J. Gibson, J. P. Vasilakos, and R. M. Kedl The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-{alpha} Production in CD11c+CD11b+CD8- Dendritic Cells J. Immunol., August 1, 2003; 171(3): 1156 - 1163. [Abstract] [Full Text] [PDF]
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D. Rodriguez, A. C. Keller, E. L. Faquim-Mauro, M. S. de Macedo, F. Q. Cunha, J. Lefort, B. B. Vargaftig, and M. Russo Bacterial Lipopolysaccharide Signaling Through Toll-Like Receptor 4 Suppresses Asthma-Like Responses Via Nitric Oxide Synthase 2 Activity J. Immunol., July 15, 2003; 171(2): 1001 - 1008. [Abstract] [Full Text] [PDF]
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J.-X. Gao, X. Liu, J. Wen, H. Zhang, J. Durbin, Y. Liu, and P. Zheng Differentiation of Monocytic Cell Clones into CD8{alpha}+ Dendritic Cells (DC) Suggests that Monocytes Can Be Direct Precursors for Both CD8{alpha}+ and CD8{alpha}- DC in the Mouse J. Immunol., June 15, 2003; 170(12): 5927 - 5935. [Abstract] [Full Text] [PDF]
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H. Hackstein, T. Taner, A. F. Zahorchak, A. E. Morelli, A. J. Logar, A. Gessner, and A. W. Thomson Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo Blood, June 1, 2003; 101(11): 4457 - 4463. [Abstract] [Full Text] [PDF]
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T. Kambayashi, E. Assarsson, A. E. Lukacher, H.-G. Ljunggren, and P. E. Jensen Memory CD8+ T Cells Provide an Early Source of IFN-{gamma} J. Immunol., March 1, 2003; 170(5): 2399 - 2408. [Abstract] [Full Text] [PDF]
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 T. Morichika, H. K. Takahashi, H. Iwagaki, T. Yoshino, R. Tamura, M. Yokoyama, S. Mori, T. Akagi, M. Nishibori, and N. Tanaka Histamine Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-{alpha} Production in an Intercellular Adhesion Molecule-1- and B7.1-Dependent Manner J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 624 - 633. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Kanto, T. Tatsumi, V. Groh, T. Spies, T. Miyagi, T. Suzuki, Y. Sasaki, and N. Hayashi Critical Role of MHC Class I-Related Chain A and B Expression on IFN-{alpha}-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection J. Immunol., February 1, 2003; 170(3): 1249 - 1256. [Abstract] [Full Text] [PDF]
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C. Sedlik, D. Orbach, P. Veron, E. Schweighoffer, F. Colucci, R. Gamberale, A. Ioan-Facsinay, S. Verbeek, P. Ricciardi-Castagnoli, C. Bonnerot, et al. A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation J. Immunol., January 15, 2003; 170(2): 846 - 852. [Abstract] [Full Text] [PDF]
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A. E. Morelli, A. T. Larregina, W. J. Shufesky, A. F. Zahorchak, A. J. Logar, G. D. Papworth, Z. Wang, S. C. Watkins, L. D. Falo Jr, and A. W. Thomson Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production Blood, January 15, 2003; 101(2): 611 - 620. [Abstract] [Full Text] [PDF]
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H. Matsue, C. Yang, K. Matsue, D. Edelbaum, M. Mummert, and A. Takashima Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation J. Immunol., October 1, 2002; 169(7): 3555 - 3564. [Abstract] [Full Text] [PDF]
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M. J. Loza and B. Perussia Peripheral Immature CD2-/low T Cell Development from Type 2 to Type 1 Cytokine Production J. Immunol., September 15, 2002; 169(6): 3061 - 3068. [Abstract] [Full Text] [PDF]
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M. Menges, S. Ro{beta}ner, C. Voigtlander, H. Schindler, N. A. Kukutsch, C. Bogdan, K. Erb, G. Schuler, and M. B. Lutz Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor {alpha} Induce Antigen-specific Protection of Mice from Autoimmunity J. Exp. Med., December 31, 2001; 195(1): 15 - 22. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
), or
CD86+ B10 DC (
), assessed using C3H splenic T cells as
responders. B10 (H2b) DC (d 7) were set up at graded
concentrations with 2 × 105 responder naive C3H
(H2k) T cells, and the cultures were maintained for 72 hours. [3H]TdR was added 18 hours before harvesting. The
MLR stimulatory activity of freshly isolated allogeneic (B10 [
])
or syngeneic (C3H [
]) bulk spleen cells is also shown. Results are
expressed as mean cpm ± 1 SD and are representative of at least 3 separate experiments.
CD11c+CD86
, CD11c+CD86
, CD11c+CD86+ DCs. Densitometric values were
pooled from 3 separate experiments.
, DC + anti-CD40. Densitometric values (means ± 1 SD) were pooled from 3 separate experiments.
B,