|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 90 No. 4 (August 15), 1997:
pp. 1458-1470
CD34+ Hematopoietic Progenitors From Human Cord Blood Differentiate Along Two Independent Dendritic Cell Pathways in Response to Granulocyte-Macrophage Colony-Stimulating Factor Plus Tumor Necrosis Factor  : II. Functional Analysis
By
Christophe Caux,
Catherine Massacrier,
Béatrice Vanbervliet,
Bertrand Dubois,
Isabelle Durand,
Marina Cella,
Antonio Lanzavecchia, and
Jacques Banchereau
From Schering-Plough, Laboratory for Immunological Research, Dardilly, France and the Basel Institute for Immunology, Basel, Switzerland.
 |
ABSTRACT |
In response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor  , cord blood CD34+ hematopoietic progenitor cells differentiate along two unrelated dendritic cell (DC) pathways: (1) the Langerhans cells (LCs), which are characterized by the expression of CD1a, Birbeck granules, the Lag antigen, and E cadherin; and (2) CD14+ cell-derived DCs, characterized by the expression of CD1a, CD9, CD68, CD2, and factor XIIIa (Caux et al, J Exp Med 184:695, 1996). The present study investigates the functions of each population. Although the two populations are equally potent in stimulating naive CD45RA cord blood T cells through apparently identical mechanisms, each also displays specific activities. In particular CD14-derived DCs show a potent and long-lasting (from day 8 to day 13) antigen uptake activity (fluorescein isothiocyanate dextran or peroxidase) that is about 10-fold higher than that of CD1a+ cells, which is restricted to the immature stage (day 6). The antigen capture is exclusively mediated by receptors for mannose polymers. The high efficiency of antigen capture of CD14-derived cells is coregulated with the expression of nonspecific esterase activity, a tracer of lysosomial compartment. In contrast, the CD1a+ population never expresses nonspecific esterase activity. The most striking difference is the unique capacity of CD14-derived DCs to induce naive B cells to differentiate into IgM-secreting cells, in response to CD40 triggering and interleukin-2. Thus, although the two populations can allow T-cell priming, initiation of humoral responses might be preferentially regulated by the CD14-derived DCs. Altogether, those results show that different pathways of DC development might exist in vivo: (1) the LC type, which might be mainly involved in cellular immune responses, and (2) the CD14-derived DC related to dermal DCs or circulating blood DCs, which could be involved in humoral immune responses.
| |
INTRODUCTION |
REQUIRED FOR THE initiation of immune responses, dendritic cells (DCs) are professional antigen presenting cells, present at trace level in all organs.1 It is believed that the various DCs encountered in the different organs are interconnected by defined pathways of migration and represent different stages of maturation of a unique DC lineage. In the periphery, during an injury, DCs such as the Langerhans cells (LCs) in the epidermis capture the antigen and then migrate through the afferent lymph stream to the T-cell-rich areas of the regional draining lymph nodes where they present the processed antigen to naive T cells and induce an antigen-specific primary T-cell response.2-8 This T-cell activation is then followed by cognate interactions between antigen-specific T and B cells yielding to primary antibody formation.9-11 These functions of DCs have been shown in vivo in mice using mainly splenic DCs.12-16 The recent description of different DC populations within secondary lymphoid organs such as spleen,17 Peyer Patches,18 and tonsil19 raises the possibility that the different phases of immune responses (T-cell priming and primary antibody responses) might be regulated by different DC populations. In this respect, thymic DCs in mice appear to originate from a hematopoietic progenitor with lymphoid but no myeloid potential.20 This subset might have been identified also in humans.21 In contrast, DCs related to LCs generated in vitro from hematopoietic progenitors using granulocyte-macrophage colony-stimulating factor (GM-CSF ) in mice22-24 or GM-CSF plus tumor necrosis factor (TNF ) in humans25,26 appear to originate from a progenitor common to monocytes and granulocytes.27-29 Thus, different lineages of DCs may exist.
In a recent study,30 we showed that human myeloid progenitors can differentiate in a unique culture condition (GM-CSF plus TNF ), along two unrelated DC pathways: the LC, which is characterized by the expression of CD1a, Lag, Birbeck granules (BGs), and E cadherin; and a CD14-derived DC, which is characterized by the expression of CD1a, CD9, CD2, and factor XIIIa. In the present study, we investigate the respective function of the two populations. We show that these two subsets display the properties expected for DCs, including priming of naive T cells and antigen capture, but in cocultures with CD40-activated naive B cells only the CD14-derived DCs can induce the production of IgM in response to interleukin-2 (IL-2). These results might suggest that initiation of humoral responses is possibly preferentially regulated by the CD14-derived DC type, whereas T-cell priming can be controlled by both populations.
| |
MATERIALS AND METHODS |
Hematopoietic factors, reagents, and cell lines.
Recombinant human (rh) GM-CSF (specific activity, 2 × 106 U/mg; Schering-Plough Research Institute, Kenilworth, NJ) was used at a saturation concentration of 100 ng/mL (200 U/mL). rhTNF (specific activity, 2 × 107 U/mg; Genzyme, Boston, MA) was used at an optimal concentration of 2.5 ng/mL (50 U/mL).31 rh stem cell factor (rhSCF; specific activity 4 × 105 U/mg; R&D, Abington, UK) was used at an optimal concentration of 25 ng/mL. rhIL-2 (specific activity, 3 × 106 U/mg; Amgen, Thousand Oaks, CA) was used at an optimal concentration of 20 U/mL. Staphylococcal enterotoxin A (SEA; Sigma, St Louis, MO) was used at 1 ng/mL. rhIL-10 (specific activity, 2 × 107 U/mg, Schering-Plough Research Institute) was used at 50 ng/mL. Monoclonal antibodies (MoAbs) against CD80 (Mab 104),32 and CD86 (IT2-2; Pharmingen, San Diego, CA) were used at 10 µg/mL. Lysine-fixable fluorescein isothiocyanate (FITC) dextran (Molecular Probes Inc, Eugene, OR) was used in most experiments at 0.1 mg/mL. Horseradish peroxidase (HRP) was purchased from Sigma. Mannan from Saccharomyces cerevisiae (Sigma) was used at 1 mg/mL. Anti-mannose receptor (3.29, generated in the laboratory of Dr Lanzavecchia, Basel, Switzerland) was used as a hybridoma supernatant at 10% and 50% (vol/vol).
View larger version (K):
[in this window]
[in a new window]
| Fig 1.
Efficient naive T-cell proliferation is induced by CD1a-or CD14-derived DCs. Cord blood CD34+ HPCs were cultured in the presence of GM-CSF plus TNF. After 5 to 6 days cells were collected, processed for double staining using anti-CD14-PE and anti-CD1a-FITC, and FACS-sorted into CD14-CD1a+ and CD14+CD1a-. Sorted cells were seeded in the presence of GM-CSF plus TNF (1 to 2 × 105 cells/mL) for 6 to 7 additional days, with last medium changes being performed at day 10. (A and B) At the indicated time points, independent aliquots of cells were harvested and used, after irradiation (30 Gy), as stimulator cells for CD45RA+ CD4+ naive cord blood T cells (2 × 104 cells/well). For day 0, uncultured CD34+ HPCs were used as stimulator cells. T cells from the same batches were used each time after thawing. Proliferation of allogeneic T cells induced by 103 stimulator cells is shown (A). Proliferation of syngeneic T cells in absence or presence of 1 ng/mL SEA induced by 102 stimulator cells is shown in (B). (C and D) Cells were recovered at day 12 and used after irradiation (30 Gy) as stimulator cells for cord blood CD45RA+ CD4+ T cells (2 × 104 cells/well; C) or cord blood CD8+ T cells (2 × 104 cells/well; D). Proliferation was shown by 3H-TdR uptake after 5 days of culture. Results are expressed as mean cpm ± SD of triplicate cultures. Results of each panel are representative of three experiments or more.
|
|
The murine CD40 ligand-transfected cell line (CD40-L L cells) was produced in the laboratory and used as stimulator of B-cell proliferation and differentiation.33
Collection and purification of cord blood CD34+ HPCs.
Umbilical cord blood samples were obtained according to institutional guidelines. Cells bearing CD34 antigen were isolated from mononuclear fractions34,35 through positive selection using anti-CD34 MoAbs (Immu-133.3; Immunotech, Marseille, France) and goat antimouse IgG-coated microbeads (Miltenyi Biotec GmBH, Bergish Gladbach, Germany). Isolation of CD34+ progenitors was achieved using Minimacs separation columns (Miltenyi Biotec) as described.34,35 In all experiments the isolated cells were 80% to 99% CD34+ as judged by staining with anti-CD34 MoAb. After purification, CD34+ cells were cryopreserved in 10% dimethyl sulfoxide.
View larger version (K):
[in this window]
[in a new window]
| Fig 2.
Both CD1a- or CD14-derived DC-induced T-cell priming are inhibited by anti-CD86 or IL-10. CD1a- and CD14-derived DC subsets were obtained as described in Materials and Methods and in the legend to Fig 1. At day 14, cells were used after irradiation (30 Gy) as stimulator cells (103 cells/well) for cord blood CD4+ T cells (2 × 104 cells/well). (A) Experiments were performed in the presence of 10 µg/mL of anti-CD80 (Mab 104), anti-CD86 (IT2-2), anti-CD80 plus anti-CD86, or isotype match control. (B) Experiments were performed in the presence or absence of IL-10 (50 ng/mL). Proliferation was shown by 3H-TdR uptake after 5 days of culture. Results are expressed as mean cpm ± SD of triplicate cultures. Results of each panel are representative of three experiments.
|
|
View larger version (K):
[in this window]
[in a new window]
| Fig 3.
Differential uptake of FITC dextran by CD1a- and CD14-derived DCs during maturation. Cord blood CD34+ HPCs were cultured in the presence of GM-CSF plus TNF. After 5 to 6 days, cells were collected and half were processed for double staining, using anti-CD14-PE and anti-CD1a-FITC, and FACS-sorted into CD14+CD1a-. Half of the cells were processed for double staining, using anti-CD14-FITC and anti-CD1a-PE, and FACS-sorted into CD14-CD1a+. Using this procedure, the sorted populations were labeled with PE, thus, avoiding interferences with FITC dextran. Sorted cells were seeded in the presence of GM-CSF plus TNF (1 to 2 × 105 cells/mL) for 6 to 7 additional days with last medium changes being performed at day 10. At the indicated time points, cells were processed for FITC dextran uptake. Cells were incubated in medium containing 0.1 mg/mL FITC dextran at 37°C for 15 minutes, washed with cold medium, and analyzed on a FACScan. For days 4 and 6, FITC dextran uptake was performed on total populations by double color fluorescence using anti-CD1a-PE or anti-CD14-PE. The same parameters of the FACScan were used during the kinetic. Results are representative of three independent experiments.
|
|
View larger version (K):
[in this window]
[in a new window]
| Fig 4.
Parameters of FITC dextran accumulation in day-6 CD1a-DC precursors and day-11 CD14-derived DCs. (A) MFI of histograms shown in Fig 3. The background fluorescence (cells pulsed at 4°C) was subtracted. (B and C) Cells were pulsed with 0.1 mg/mL FITC dextran at 37°C for various times, washed with cold medium, and analyzed on a FACScan. Uptake of FITC dextran was performed at day 6 on total population by double color fluorescence using, after pulse with FITC dextran, anti-CD1a-PE (CD1a+ cells), anti-CD14-PE (CD14+ cells), and anti-CD1a-PE plus anti-CD14-PE (CD14-CD1a- cells; B). Uptake of FITC dextran was performed at day 11 by single color fluorescence on the sorted populations (C). (D and E) Cells were pulsed with 0.1 mg/mL FITC dextran for 15 minutes at 37°C, washed with cold medium, and analyzed immediately or after culture at 37°C for various times in marker-free medium. Chase was performed at day 6 on total populations by double color fluorescence (D). Chase was performed at day 11 by single color fluorescence on the sorted populations (E). Results of each panel are representative of three experiments or more.
|
|
View larger version (K):
[in this window]
[in a new window]
| Fig 5.
FITC dextran and HRP uptake by the two DC subpopulations is mediated through receptors for mannose polymers. The experiments of FITC dextran uptake were performed on day-6 CD1a precursors by double color fluorescence (A and C) and on day-11 CD14-derived DCs (B and D; see legend to Figs 3 and 4). The uptake of HRP was performed on day-6 and day-11 CD1a+- and CD14-derived cells (E and F ). (A and B) Cells were pulsed for 15 minutes at 37°C with various concentrations of FITC dextran in the absence or in the presence of 1 mg/mL mannan. (C and D) Cells were pulsed for various times at 37°C with 0.1 mg/mL FITC dextran in the absence or in the presence of 1 mg/mL mannan. (E and F ) Cells were pulsed for 15 minutes at 37°C with various concentrations of HRP in the absence or in the presence of 1 mg/mL mannan. Results of each panel are representative of three experiments or more.
|
|
Purification of cord blood T cells.
Mononuclear cells were isolated from cord blood and depleted of adherent cells by overnight adherence to plastic in complete medium at 1 × 106 cells/mL. Total CD4 T lymphocytes were then purified by immunomagnetic depletion using a cocktail of MoAbs IOM2 (CD14), ION16 (CD16), ION2 (HLA-DR; Immunotech, Marseille, France), NKH1 (CD56), OKT8 (CD8; Ortho Diagnostic System, Raritan, NJ), 4G7 (CD19), and Mab 89 (CD40).36 For CD45RA+ CD4+ T-cell purification UCHL-1 (CD45RO) was added to the cocktail of MoAbs. For CD8+ T-cell purification, anti-CD4 (Sigma) was used instead of anti-CD8. After two rounds of bead depletion, the purity of CD4+ T cells was routinely higher than 95% and that of CD45RA+ CD4+ T cells and CD8+ T cells was higher than 90%.
Isolation of tonsillar IgD+ B cells.
Mononuclear cells from tonsils were isolated by a standard Ficoll-Hypaque (density, 1,077 g/mL) gradient method. Tonsillar B cells were first enriched in the E- fraction and submitted to anti-CD2, anti-CD4, anti-CD8, anti-CD14, anti-CD16 MoAb negative selection with magnetic beads coated with antimouse IgG (Dynabeads; Dynal, Oslo, Norway). In the isolated population, greater than 99% expressed CD19 or CD20 and less than 1% expressed CD2 or CD14 Ags. Isolation of sIgD+ B-cell subpopulation was performed using a preparative magnetic cell sorter (Miltenyi Biotec). The separation based on sIgD expression has been described in details elsewhere.37 IgD was expressed on greater than 99% of the sIgD+ B-cell subpopulation as assessed by fluorescence analysis using a FACScan (Becton Dickinson, Sunnyvale, CA).
Liquid cultures for DC generation.
Cultures were established in the presence of SCF, GM-CSF, and TNF, as described,25,26 in endotoxin-free medium consisting of RPMI 1640 (GIBCO, Grand Island, NY) supplemented with 10% (vol/vol) heat-inactivated fetal bovine serum (FBS; Flow Laboratories, Irvine, UK), 10 mmol/L HEPES, 2 mmol/L L-glutamine, 5 × 10-5 mol/L 2-mercaptoethanol, penicillin (100 U/mL), and streptomycin (100 µg/mL; referred to as complete medium).
After thawing, CD34+ cells were seeded for expansion in 25- to 75-cm2 culture vessels (Linbro; Flow Laboratories, Mc Lean, VA) at 2 × 104 cells/mL. Optimal conditions were maintained by splitting these cultures at day 4 with medium containing fresh GM-CSF and TNF (cell concentration, 1 to 3 × 105 cells/mL). For most experiments, cells were routinely collected after 5 to 6 days of culture for fluorescence-activated cell sorting (FACS). Culture medium was supplemented with 2.5% AB+ pooled human serum at the initiation of the cultures, and by day 5 to 6 human serum was washed away.
Isolation of CD1a and CD14 DC precursors by FACS.
After 5 to 6 days of culture in the presence of SCF, GM-CSF, and TNF , cells were collected and labeled with FITC-conjugated OKT6 (CD1a; Ortho) and phycoerythrin (PE)-conjugated Leu-M3 (CD14; Becton Dickinson, San Jose, CA), as described.30 Cells were separated according to CD1a and CD14 expression into CD14+CD1a-, CD14-CD1a+ fractions using a FACStarplus (laser setting: power, 250 mW, excitation wavelength 488 nm; Becton Dickinson, Sunnyvale, CA). For some specific experiments (see FITC-dextran capture) FACS of CD14-CD1a+ cells was performed after staining with PE-conjugated T6 (CD1a; Coulter, Hialeah, FL) and FITC-conjugated Leu-M3 (CD14; Becton Dickinson, San Jose, CA). All the procedures of staining and sorting were performed in the presence of 0.5 mmol/L EDTA to avoid cell aggregation. Reanalysis of the sorted populations showed a purity higher than 98%, the other cells were undetermined myeloid cells (T cells could never be detected even by polymerase chain reaction [PCR]).
Sorted cells were seeded in the presence of GM-CSF plus TNF (1 to 2 × 105 cells/mL) for 6 to 7 additional days with a last medium change being performed at day 10. Cells were routinely collected between day 11 and day 14; eventually adherent cells were recovered using a 0.5-mmol/L EDTA solution.
Quantitation of endocytosis using FITC dextran capture followed by FACS analysis.
The procedure for measuring FITC dextran uptake was previously described.38 Briefly, at the indicated time points cells were harvested and resuspended in 10% FBS medium buffered with 25 mmol/L HEPES at 37°C in a water bath. FITC dextran was added at the final concentration of 0.1 mg/mL and for 15 minutes, if not otherwise indicated. The cells were washed four times with cold phosphate-buffered saline (PBS) containing 1% FBS and 0.01% NaN3. For experiments performed on total populations, at day 4 and 6 double staining was made using anti-CD1a-PE or anti-CD14-PE. In some experiments, the cells were pulsed at 37°C; washed four times in cold medium, and cultured at 37°C for different times in marker-free medium. After staining, cells were analyzed on a FACScan. When the results were expressed as mean fluorescence intensity, the background (cells pulsed with FITC dextran at 4°C) was subtracted, if not otherwise indicated.
Quantitation of endocytosis by HRP capture.
The procedure for measuring HRP uptake was previously described.38 Briefly, at the indicated time points, cells were harvested and resuspended in 10% FBS medium buffered with 25 mmol/L HEPES at 37°C in a water bath. HRP was added at the final concentration of 0.1 µg/mL to 0.1 mg/mL for 15 minutes. The cells were washed four times with cold PBS containing 1% FBS and 0.01% NaN3 and lysed with 0.05% Triton X-100 in 10 mmol/L Tris buffer, pH 7.4, for 30 minutes. After centrifugation (10 minutes, 600g), enzyme activity of the lysate was measured using o-phenylenediamine and H2O2 as substrate with reference to a standard curve.
Nonspecific esterase staining.
Cells were cytocentrifuged for 5 minutes at 500 rpm on a microscope slide. Slides were used for nonspecific esterase staining (-naphthyl acetate esterase staining kit; Sigma).
T-cell proliferation assay.
During culture in GM-CSF plus TNF, CD34+ HPC-derived cells were collected and, after irradiation (30 Gy), were used as stimulator cells for resting allogeneic or syngeneic T cells (2 × 104 per well), as described.39,40 After 5 days of incubation, cells were pulsed with 1 µCi of 3H-TdR (specific activity, 25 Ci/mmol) per well, for the last 8 hours; harvested; and counted. Tests were performed in triplicate, and results were expressed as mean counts per minute (cpm) ± standard deviation (SD). The levels of 3H-TdR uptake by stimulator cells alone were always below 100 cpm.
Coculture of B cells and DCs.
A total of 2.5 × 103 irradiated CD40-L-transfected L cells (75 Gy) were seeded together with 104 IgD+ B lymphocytes in the presence or absence of irradiated (30 Gy) DC subsets (3 × 103 per well) in 96-well culture plates (Nunc, Roskilde, Denmark), as described.41 For measurement of proliferation, cells were pulsed after 5 days of incubation with 1 µCi of 3H-TdR (specific activity, 25 Ci/mmol) per well for the last 8 hours, harvested, and counted. Tests were performed in triplicate, and results were expressed as mean cpm ± SD. The levels of 3H-TdR uptake by stimulator cells alone were always below 100 cpm. For determination of IgM production, supernatants were recovered after 15 days and used for indirect enzyme-linked immunosorbent assay (ELISA).42 Control for emergence of contaminating T cells were routinely performed, and CD3+ cells were never detected at any time point tested.41
View larger version (K):
[in this window]
[in a new window]
| Fig 6.
FITC dextran and HRP uptake by the two DC subpopulations are mediated through mannose receptors. (A and B) The experiments were performed on day-6 CD1a precursors by double color fluorescence (A) and on day-11 CD14-derived DCs (B). Cells were pulsed for 15 minutes at 37°C with 0.1 mg/mL FITC dextran in the presence of medium, 10% supernatant MoAb anti-mannose receptor (anti-MR), 50% supernatant MoAb anti-MR, or 1 mg/mL mannan. (C) Cells were processed at day 6 for double staining using anti-MR shown by PE-conjugated antimouse Ig. Then, after saturation in 5% mouse serum, cells were stained with anti-CD14-FITC or anti-CD1a-FITC. A total of 20,000 events were acquired. Histograms show PE staining gated on CD1a+ cells (left) or on CD14+ cells (right). (D) CD1a- and CD14-derived DC subsets, obtained as described in Materials and Methods and in the legend to Fig 1, were processed at day 11 for single staining using anti-MR shown by PE-conjugated antimouse Ig. A total of 5,000 events were acquired. White histograms represent isotype matched control. Results of each panel are representative of three experiments or more.
|
|
CD40 activation of DC subsets.
A total of 105 CD1a- or CD14-derived DCs were cultured with 2.5 × 104 irradiated CD40-L-transfected L cells (or control L cells) in a final volume of 1 mL in 24-well culture plates, as described.43 After 4 days of culture, cells were gently recovered and used for staining experiments.
Cytofluorometric cell-surface phenotyping.
Cells were processed for double staining (day 6) or single staining (day 12 sorted populations), as previously described.30
Binding of immune complexes.
Cells were incubated at 4°C for 15 minutes with 5 µg/mL FITC-coupled streptavidin (Sigma) and 100 µg/mL mouse MoAb anti-FITC (clone FL-D6, IgG1; Sigma). Controls were performed with FITC streptavidin alone or with FITC MoAb isotype control. In some experiments cells were first incubated for 15 minutes with 50 µg/mL of a blocking MoAb against CD32 (clone IV.3; Medarex, Annandale, NJ) followed by 15 minutes with 5 µg/mL FITC-coupled streptavidin and 100 µg/mL mouse MoAb anti-FITC.
| |
RESULTS |
The two DC subpopulations display comparable T-cell activation properties.
First, we have investigated the effects of the two in vitro-generated DC populations on the induction of proliferation of allogeneic naive CD45RA+ cord blood T cells. The stimulatory potential of the two DC populations (103 stimulatory cells for 2 × 104 T cells) was determined at day 6 (day of FACS), day 10, day 13, and day 16. As shown in Fig 1A, the stimulatory potential of the CD1a-derived population is detectable at day 6, peaks around day 10, and is maintained until day 16 (latest time tested). The CD14-derived population lacks stimulatory activity at day 6 but displays such a potential from day 9 to 16. Comparable stimulatory properties of the two populations are observed when syngeneic CD45RA+ cord blood T cells are cocultured in the presence of superantigens (SEA is shown in Fig 1B). At day 14, both populations are equally able to induce proliferation of CD45RA CD4+ T cells with half maximal proliferation observed with 300 to 600 DCs (Fig 1C). Also, at day 14 both DC populations are comparable in their capacity to stimulate the proliferation of CD8+ T cells. Higher numbers of stimulator cells were required (103 DCs) when compared with CD4+ T cells (Fig 1D). However, further addition of IL-2 reduced the number of stimulator cells to 300 cells (not shown).
We next analyzed whether naive T-cell activation induced by the two DC populations was involving identical molecular interactions. As shown in Fig 2A, in both cases, activation of naive T cells is blocked by 80% using MoAbs against CD86, whereas MoAbs against CD80 have no effect, as previously described, with unseparated DCs.39 Thus CD86 appears to act as the major ligand for CD28 on the two DC subsets. Furthermore, addition of exogenous IL-10 reduces by 70% to 80% the T-cell proliferation in both cases (Fig 2B), as previously described, for unseparated DCs.40
Thus, both DC populations can induce considerable naive T-cell proliferation through apparently common pathways with CD14-derived DCs displaying a delayed stimulatory potential.
CD14-derived DCs capture soluble antigen more efficiently than CD1a-derived DCs.
The ability of the two populations to capture soluble antigen was analyzed during cell maturation using FITC dextran and flow cytometry38 (Figs 3 and 4A). At day 4, none of the subsets can significantly capture FITC dextran. The CD1a+ precursors show FITC-dextran uptake at day 6 with a majority of cells being moderately labeled. This capacity is downregulated at day 8 and lost at day 10 and later, even after 1 hour of exposure to FITC dextran (Fig 4C). At day 6, 12% to 35% (range of 6 experiments) of the CD14+ precursors accumulate FITC dextran and 42% to 71% of cells do so at day 8. At day 10, 94% to 100% of cells capture FITC dextran so efficiently that it can be detected after a contact as short as 3 minutes (Fig 4C). After 10 days of culture, CD14-derived DCs progressively lose their capture capacity with 12% to 35% of cells labeled at day 16. This heterogeneity in the capacity to form antigen uptake among CD14-derived DCs at day 16 suggests the coexistence of two populations, probably two stages of maturation. The capture of FITC dextran, at day 6 and day 11, appears to be a linear function of time, and CD14-derived DCs are 8 to 12 times more efficient than day 6 CD1a+ precursors (Fig 4B and C). Similar results were observed using HRP rather than FITC dextran (Fig 5E and F ). The FITC-dextran uptake is restricted to CD1a and CD14 subpopulations as CD14-CD1a- cells lack such a capacity (Fig 4B, day 6). Pulse chase experiments show that the two DC populations (day 6 for CD1a+, Fig 4D; and day 11 for CD14+, Fig 4E) retained more than 80% of the FITC dextran for several hours (up to 16 hours, not shown), showing that the captured antigen is not immediately released.
View larger version (K):
[in this window]
[in a new window]
| Fig 7.
Only CD14-derived DCs display nonspecific esterase activity. The CD1a- (A, B, C, D, and E) and CD14- (F, G, H, I, and J) derived DC subsets were obtained as described in Materials and Methods and in the legend to Fig 1. Cells were processed at day 6 (A and F ), day 8 (B and G), day 10 (C and H), day 13 (D and I), and day 16 (E and J) for nonspecific esterase staining. Original magnification × 400. Results are representative of three experiments.
|
|
These results show that the CD1a-derived DCs display a limited antigen capture capacity that is restricted to the early stages of differentiation, whereas the CD14-derived DCs show a high antigen capture capacity that is long lasting during their maturation.
View larger version (K):
[in this window]
[in a new window]
| Fig 8.
Only CD14-derived DCs can induce CD40-activated naive B cells to differentiate into IgM secreting cells. The CD1a- and CD14-derived DC subsets were obtained as described in Materials and Methods and in the legend to Fig 1. A total of 104 highly purified IgD+ B cells were cultured over 2,500 irradiated CD40-L-transfected L cells in the presence or absence of DC subsets. Proliferation was measured by 3H-TdR incorporation at day 6. Supernatants were harvested after 15 days of culture and assayed for the presence of IgM. (A) DC subsets were recovered at day 12 and used as stimulator cells (3,000 cells/well) for IgD+ B-cell proliferation in the absence or presence of 20 U/mL IL-2. (B) DC subsets were recovered at day 12 and used as stimulator cells (3,000 cells per well) for IgD+ B cell differentiation in the absence or presence of 20 U/mL IL-2. (C) DC subsets were recovered at day 12, and 300, 1,000, and 3,000 cells/well were used as stimulator cells for IgD+ B-cell differentiation in the presence of 20 U/mL IL-2. (D) DC subsets were recovered at the time point indicated and used as stimulator cells (3,000 cells/well) for IgD+ B-cell differentiation in the presence of 20 U/mL IL-2. IgM levels are expressed as mean ± SD of triplicate cultures. Results of each panel are representative of three experiments or more.
|
|
Both CD1a+ cells and CD14-derived DCs capture FITC dextran through a receptor-mediated mechanism.
We next wondered whether the day-6 CD1a+ cells and the day-11 CD14-derived DCs captured antigen through either fluid phase pinocytosis or receptor-mediated endocytosis. The amount of FITC dextran (Fig 5A and B) and HRP (Fig 5E and F ) accumulated by the two DC populations showed a clear saturation at increasing doses of the marker, thus suggesting a receptor-mediated mechanism. The uptake of FITC-dextran and HRP by the two populations is completely blocked in the presence of mannan (1 mg/mL) even for high concentration of tracer (1 mg/mL). The uptake of FITC dextran is usually blocked by a twofold to threefold excess of mannan (not shown). Kinetics experiments (1 to 60 minutes) show that for both populations FITC dextran uptake is entirely blocked by an excess of mannan (1 mg/mL mannan for 0.1 mg/mL FITC dextran, shown in Fig 5C and D), even after 1 hour of exposure. Finally, an antibody against the mannose-receptor (MR), that blocks MR dependent FITC dextran capture,38 inhibits by about 80% the FITC dextran capture of the two populations (hybridoma supernatant used at 50%; Fig 6A and B). The FITC dextran capture of the day-6 CD14+ precursors follows the rules of their more mature day-11 progeny (not shown). As shown in Fig 6C and D, MR is strongly expressed on day-6 CD1a+ precursors but is lost on day-11 CD1a-derived DCs. In contrast, on CD14-derived cells, MR expression is detected at day 6 and peaks at day 11.
Thus, the uptake of FITC dextran and HRP by the two DC populations is exclusively receptor mediated and correlates with the level of MR expression.
Only CD14-derived DCs display nonspecific esterase activity.
The two populations were then processed, from day 6 to day 16, for detection of nonspecific esterase (NSE) activity. As shown in Fig 7, the CD1a-derived DCs never display any significant NSE activity, whereas, in sharp contrast, the CD14-derived DCs show NSE activity. At day 6, 20% to 35% of CD14+ cells express a moderate level of NSE activity, and from day 9 to 12 the proportion of NSE expressing cells increases up to 100% (range 80 to 100; n), and the level of activity per cell increases. From day 13 to 16, the frequency of NSE expressing cells decreases (20% to 50%), and the level of activity per cell decreases as well. At day 16, the NSE activity appears to be associated with intracytoplasmic structures, possibly lysosomes.
View larger version (K):
[in this window]
[in a new window]
| Fig 9.
CD40 triggering upregulates CD25 specifically on CD14-derived DCs. The CD1a- (upper panels) and CD14- (lower panels) derived DC subsets were obtained as described in Materials and Methods and in the legend to Fig 1. At day 12, DC subsets were recovered and cultured over CD40-L-transfected L cells on control L cells (2 × 104 LCs for 1 × 105 DCs) in the presence of GM-CSF for 4 days. Then cells were processed for staining using anti-CD25-PE, anti-CD86-PE, and isotype match control. A total of 5,000 events were acquired. White histograms show phenotype over control L cells and black histograms show phenotype over CD40-L transfected L cells. Results are representative of three experiments.
|
|
Thus, CD1a-derived DCs never express NSE activity, whereas CD14-derived DCs express transiently a high NSE activity that parallels their strong antigen uptake capacity.
Only CD14-derived DCs can induce CD40-activated naive B cells to differentiate into IgM secreting cells.
We have previously described that in vitro generated DCs can enhance the proliferation and the differentiation of naive B cells activated through CD40.41 As shown in Fig 8A, in the absence of exogenous cytokine, both DC subsets increase naive B-cell proliferation by threefold (range 2 to 5). In contrast, the enhancing effect of IL-2, which is DC dependent, is only observed in the presence of CD14-derived DCs (fold enhancement because of IL-2; medium, 1.0; CD1a+, 1.1; CD14+, 2.2). In response to IL-2, CD40 triggering alone does not allow naive B cells to produce significant levels of IgM. In contrast, addition of DCs induces a strong IgM production (30 to 80 µg/mL, range from 6 experiments; Fig 8B). In the absence of IL-2 (Fig 8B) or CD40 triggering (data not shown) no IgM secretion is detectable. Interestingly, only CD14-derived DCs are able to induce IgM production by naive B cells, and as few as 300 CD14-derived DCs induce the production of 5 to 20 µg/mL IgM (ranges from 6 experiments) (Fig 8C). Although CD14-derived DCs can induce IgD+ B-cell differentiation as early as day 6, this activity appears optimal at day 13 (Fig 8D). At each time point tested, CD1a-derived DCs do not induce IgM synthesis by IgD+ B cell. Of note, CD3+ T cells are never detected at any time points tested.41
Although the two DC populations are sensitive to CD40 engagement as shown by CD86 upregulation, CD25 expression is upregulated only on CD14-derived DCs (Fig 9). This result indicates that the IL-2-dependent effect of CD14-derived DCs on naive B-cell differentiation might be linked to their unique capacity to express CD25 on activation.
Those experiments show that the ability of DCs to induce naive B-cell differentiation into IgM secreting cells is restricted to the CD14-derived DCs. The unique capacity of CD14-derived DCs to express CD25 on activation suggests a role of IL-2 on DC functions.
Only CD14-derived DCs bind immune complexes.
We then wondered whether both DC populations were able to bind immune complexes. To address this issue, a complex of FITC-coupled streptavidin and mouse IgG1 MoAb anti-FITC was used. Both at days 6 and 12, CD14+ cells but not CD1a+ cells bind this complex (Fig 10A). Similar results were obtained with a complex of FITC-coupled streptavidin and goat polyclonal antistreptavidin (not shown). No staining was detected using (1) FITC-coupled streptavidin alone, (2) FITC-coupled isotype controls, and (3) a complex of FITC-coupled streptavidin and rat MoAb anti-FITC of IgM isotype (not shown). Furthermore, a blocking MoAb against CD32 abrogated the binding of the complex (Fig 10B).
View larger version (K):
[in this window]
[in a new window]
| Fig 10.
Only the CD14-derived DCs bind immune complexes. The CD1a- and CD14-derived DC subsets were obtained as described in Materials and Methods and in the legend to Fig 1. At days 6 and 12, DC subsets were recovered and were incubated at 4°C for 15 minutes with 5 µg/mL FITC-coupled streptavidin and 100 µg/mL mouse IgG1 MoAb anti-FITC. (A) Day 6, (B) day 12, and (C) day-12 CD14-derived cells were first incubated for 15 minutes with 50 µg/mL of a blocking MoAb against CD32 followed by 15 minutes with 5 µg/mL FITC-coupled streptavidin and 100 µg/mL mouse IgG1 MoAb anti-FITC. White histograms show FITC streptavidin alone. FITC-coupled isotype match controls were superposable to the white histograms.
|
|
Thus, CD14+ precursors and their progeny bind immune complexes through CD32 whereas CD1a do not, in line with their low CD32 expression.30
| |
DISCUSSION |
Recently, we showed the existence of two independent pathways of DC development yielding to (1) an epithelial DC related to LCs and (2) a monocyte-derived DC potentially related to interstitial DCs and/or peripheral blood DCs.30 In the present study, we have investigated the potential physiological relevance of these two populations through the study of their specific biological functions. Although both populations were equally potent in stimulating naive T cells through apparently identical mechanisms, each displayed the other's unique properties. In particular, CD14-derived DCs show a potent antigen uptake activity that is, at its peak, about 10-fold more efficient than that of CD1a+ precursors. In addition, antigen uptake capacity of CD14-derived DCs was long lasting (from day 8 to day 14), whereas the weak activity of CD1a+ cells was restricted to the immature stage (day 6). Modulation of uptake capacity during maturation correlates with the expression of the mannose-receptor, which is expressed at high levels on day-6 CD1a+ precursors and on day-11 CD14-derived DCs. In both DC subsets, the capture of FITC dextran and HRP is exclusively mediated through receptor for mannose polymers. It remains to be determined whether receptor-mediated endocytosis involving coated pits or macropinocytosis38 are used by these distinct DC subsets. An alternative pathway allowing antigen uptake is mediated through binding of immune complexes to CD32, a capacity restricted to CD14+ precursors and their progeny. Antigen uptake through either mannose receptors (mannosilated antigen) or through CD32 (immune complexes) allow efficient presentation to CD4+ T cells,44 suggesting that CD14+ cells might be more efficient than CD1a+ cells in presenting these forms of antigen.
The high antigen capture efficiency of CD14-derived DCs correlated with their high NSE activity, which is a tracer of lysosomial compartment characterizing scavengers. These properties, which are linked to antigen capture and degradation, precede, despite some overlaps (day 13), the upregulation of accessory molecules such as CD86 and the capacity to activate naive T cells (Fig 11), which is in accordance with the accepted scheme of DC maturation.1,45 It has to be noticed that the capacity to stimulate naive T cells, which is CD86 dependent, precedes the upregulation of CD86 expression, suggesting CD86 induction during interaction with T cells, potentially through CD40 engagement.39
View larger version (K):
[in this window]
[in a new window]
| Fig 11.
Evolution of functions during DC subpopulation maturation. The figure represents parameters of DC activities as a function of time. MFI of CD86 illustrates the progression of DC maturation. FITC dextran illustrates the capacity of antigen uptake. NSE illustrates the lysosomal activity. T-cell alloreaction illustrates the capacity to activate naive T cells. B-cell differentiation illustrates the capacity to induce naive B-cell differentiation in response to IL-2. To plot the different parameters on a same scale, values were calculated as the following ratio: (experimental value/maximal value) × 100; the maximal value being the maximal value obtained with either CD1a or CD14 populations. (A) The evolution of the CD1a-derived cells activities. (B) The evolution of the CD14-derived cells activities.
|
|
The most striking difference between the two DC populations is the unique capacity of CD14-derived DCs to induce naive B cells to differentiate into IgM secreting cells, in response to CD40 triggering and IL-2. Such a property suggests an involvement of CD14-derived DCs in the regulation of humoral responses. This regulation might occur during the initiation of primary B-cell responses, which would be consistent with in vivo studies showing that, after immunization, CD40L+ IL-2-producing CD4+ T cells are colocalized with antibody-specific secreting B cells in the extrafollicular areas of secondary lymphoid organs.46-48 In keeping with this, in vitro studies have shown IL-2 to be an important factor of primary humoral responses.49-51 However, the recent localization of typical DCs of myeloid origin within human tonsil germinal centers20 suggests an alternative interpretation. CD14-derived DCs could be related to germinal center DCs and, thus, might participate in the regulation of germinal center reaction. In this context, it is interesting that these DCs display immune complexes like CD14-derived DCs. This immune complex binding capacity might be related to native antigen carriage into the B-cell follicule.
The present studies lead us to propose that epithelial DCs (CD1a-derived LCs) migrate after antigen capture through the lymph stream to the T-cell-rich area of regional lymph nodes where they induce a primary T-cell immunization but no primary B-cell responses. This hypothesis, which suggests a preferential role of LCs in the cellular-type immune responses, is supported by the involvement of LCs in delayed-type hypersensitivity reactions observed after hapten application on the epidermis.4,6,52 In contrast, CD14-derived DCs related to monocyte-derived DCs, potentially located into tissues such as dermis or blood, might, after antigen capture, migrate through the blood (or lymph) stream into either the T-cell-rich area and/or the B-cell follicules where they could be involved in the regulation of primary B-cell responses.
The present study together with our initial one1 show the existence of two independent pathways for the development of DCs with discrete biological functions. This heterogeneity of DCs requires further understanding, particularly in view of the development of strategies aimed at using DCs as therapeutic entities to elicit immune responses specific for infectious agents as well as cancer.53,54
| |
FOOTNOTES |
Submitted January 13, 1997;
accepted April 17, 1997.
B.D. is a recipient of a grant from Fondation Marcel Mérieux, Lyon, France. Preliminary results were presented at the Keystone Meeting on Dendritic Cells, held in Taos, New Mexico, March 1995 and at the Fourth International Symposium on Dendritic Cells, held in Venice, Italy, October 1996.
Address reprint requests to Christophe Caux, PhD, Schering-Plough, 27 chemin de Peupliers, BP 11, 69571, Dardilly, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hearly marked
``advertisment'' in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
| |
ACKNOWLEDGMENT |
We are grateful to E. Garcia for FACS sorting; N. Courbière, S. Bonnet-Arnaud, and M. Vatan for editorial assistance; Doctors and colleagues from clinics and hospitals in Lyon who provide us with umbilical cord blood samples; and Dr J. Chiller for support and for discussions.
| |
REFERENCES |
1.
Steinman RM:
The dendritic cell system and its role in immunogenicity.
Annu Rev Immunol
9:271,
1991[Medline]
[Order article via Infotrieve]
2.
Mayrhofer G,
Holt PG,
Papadimitriou JM:
Functional characteristics of the veiled cells in afferent lymph from the rat intestine.
Immunology
58:379,
1986[Medline]
[Order article via Infotrieve]
3.
Bujdoso R,
Hopkins J,
Dutia BM,
Young P,
McConnell I:
Characterization of sheep afferent lymph dendritic cells and their role in antigen carriage.
J Exp Med
170:1285,
1989[Abstract/Free Full Text]
4.
Macatonia SE,
Knight SC,
Edwards AJ,
Griffiths S,
Fryer P:
Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate.
J Exp Med
166:1654,
1987[Abstract/Free Full Text]
5.
Kripke ML,
Munn CG,
Jeevan A,
Tang J-M,
Bucana C:
Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization.
J Immunol
145:2833,
1990[Abstract]
6.
Larsen CP,
Steinman RM,
Witmer-Pack MD,
Hankins DF,
Morris PJ,
Austyn JM:
Migration and maturation of Langerhans cells in skin transplants and explants.
J Exp Med
172:1483,
1990[Abstract/Free Full Text]
7.
Fossum S:
Lymph-borne dendritic leucocytes do not recirculate, but enter the lymph node paracortex to become interdigitating cells.
Scand J Immunol
27:97,
1988[Medline]
[Order article via Infotrieve]
8.
Moll H,
Fuchs H,
Blank C,
Rollinghoff M:
Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigen-specific T cells.
Eur J Immunol
23:1595,
1993[Medline]
[Order article via Infotrieve]
9.
Inaba K,
Granelli-Piperno A,
Steinman RM:
Dendritic cells are critical accessory cells for thymus-dependent antibody responses in mouse and man.
Proc Natl Acad Sci USA
80:6041,
1983[Abstract/Free Full Text]
10.
Inaba K,
Steinman RM:
Protein-specific helper T lymphocyte formation initiated by dendritic cells.
Science
229:475,
1985[Abstract/Free Full Text]
11.
Inaba K,
Witmer MD,
Steinman RM:
Clustering of dendritic cells, helper T lymphocytes, and histocompatible B cells, during primary antibody responses in vitro.
J Exp Med
160:858,
1984[Abstract/Free Full Text]
12.
Francotte M,
Urbain J:
Enhancement of antibody responses by mouse dendritic cells pulsed with tobacco mosaic virus or with rabbit antiidiotypic antibodies raised against a private rabbit idiotype.
Proc Natl Acad Sci USA
82:8149,
1985[Abstract/Free Full Text]
13.
Sornasse T,
Flamand V,
de Becker G,
Bazin H,
Tielemans F,
Thielemans K,
Urbain J,
Oberdan L,
Moser M:
Antigen-pulse dendritic cells can efficiently induce an antibody response in vivo.
J Exp Med
175:15,
1992[Abstract/Free Full Text]
14.
Berg SF,
Mjaaland S,
Fossum S:
Comparing macrophages and dendritic leukocytes as antigen-presenting cells for humoral responses in vivo by antigen targeting.
Eur J Immunol
24:1262,
1994[Medline]
[Order article via Infotrieve]
15.
Flamand V,
Sornasse T,
Thielemans K,
Demanet C,
Bakkus M,
Bazin H,
Tielemans F,
Leo O,
Urbain J,
Moser M:
Murine dendritic cells pulsed in vitro with tumor antigen induce tumor resistance in vivo.
Eur J Immunol
24:605,
1994[Medline]
[Order article via Infotrieve]
16.
Liu LM,
MacPherson GG:
Antigen acquisition by dendritic cells: Intestinal dendritic cells acquire antigen administered orally and can prime naive T cells in vivo.
J Exp Med
177:1299,
1993[Abstract/Free Full Text]
17.
Agger R,
Witmer-Pack M,
Romani N,
Stossel H,
Swiggard WJ,
Metlay JP,
Storozynsky E,
Freimuth P,
Steinman RM:
Two populations of splenic dendritic cells detected with M342, a new monoclonal to an intracellular antigen of interdigitating dendritic cells and some B lymphocytes.
J Leukocyte Biol
52:34,
1992[Abstract]
18.
Kelsall BL,
Strober W:
Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch.
J Exp Med
183:237,
1996[Abstract/Free Full Text]
19.
Grouard G,
Durand I,
Filgueira L,
Banchereau J,
Liu YJ:
Dendritic cells capable of stimulating T cells in germinal centers.
Nature
384:364,
1996[Medline]
[Order article via Infotrieve]
20.
Ardavin C,
Wu L,
Li CL,
Shortman K:
Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population.
Nature
362:761,
1993[Medline]
[Order article via Infotrieve]
21.
Galy A,
Travis M,
Cen D,
Chen B:
Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset.
Immunity
3:459,
1995[Medline]
[Order article via Infotrieve]
22.
Inaba K,
Inaba M,
Naito M,
Steinman RM:
Dendritic cells progenitors phagocytose particulates, including Bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo.
J Exp Med
178:479,
1993[Abstract/Free Full Text]
23.
Inaba K,
Inaba M,
Romani N,
Aya H,
Deguchi M,
Ikehara S,
Muramatsu S,
Steinman RM:
Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor.
J Exp Med
176:1693,
1992[Abstract/Free Full Text]
24.
Scheicher C,
Mehlig M,
Zecher R,
Reske K:
Dendritic cells from mouse bone marrow: In vitro differentiation using low doses of recombinant granulocyte-macrophage colony-stimulating factor.
J Immunol Method
154:253,
1992[Medline]
[Order article via Infotrieve]
25.
Caux C,
Dezutter-Dambuyant C,
Schmitt D,
Banchereau J:
GM-CSF and TNF- cooperate in the generation of dendritic Langerhans cells.
Nature
360:258,
1992[Medline]
[Order article via Infotrieve]
26.
Szabolcs P,
Moore MAS,
Young JW:
Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit-ligand, GM-CSF, and TNF.
J Immunol
154:5851,
1995[Abstract]
27.
Inaba K,
Inaba M,
Deguchi M,
Hagi K,
Yasumizu R,
Ikehara S,
Muramatsu S,
Steinman RM:
Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow.
Proc Natl Acad Sci USA
90:3038,
1993[Abstract/Free Full Text]
28.
Reid CDL,
Stackpoole A,
Meager A,
Tikerpae J:
Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow.
J Immunol
149:2681,
1992[Abstract]
29.
Santiago-Schwarz F,
Belilos E,
Diamond B,
Carsons SE:
TNF in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages.
J Leukocyte Biol
52:274,
1992[Abstract]
30.
Caux C,
Vanbervliet B,
Massacrier C,
Dezutter-Dambuyant C,
de Saint-Vis B,
Jacquet C,
Yoneda K,
Imamura S,
Schmitt D,
Banchereau J:
CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to GM-CSF+TNF.
J Exp Med
184:695,
1996[Abstract/Free Full Text]
31.
Caux C,
Durand I,
Moreau I,
Duvert V,
Saeland S,
Banchereau J:
TNF cooperates with IL-3 in the recruitment of a primitive subset of human CD34+ progenitors.
J Exp Med
177:1815,
1993[Abstract/Free Full Text]
32.
Vallé A,
Aubry JP,
Durand I,
Banchereau J:
IL-4 and IL-2 upregulate the expression of antigen B7, the B cell counterstructure to T cell CD28: An amplification mechanism for T-B cell interactions.
Int Immunol
3:229,
1991[Abstract/Free Full Text]
33.
Garrone P,
Neidhardt EM,
Garcia E,
Galibert L,
van Kooten C,
Banchereau J:
Fas ligation induces apoptosis of CD40-activated human B lymphocytes.
J Exp Med
182:1265,
1995[Abstract/Free Full Text]
34.
Caux C,
Saeland S,
Favre C,
Duvert V,
Mannoni P,
Banchereau J:
Tumor necrosis factor-alpha strongly potentiates interleukin-3 and granulocyte-macrophage colony-stimulating factor-induced proliferation of human CD34+ hematopoietic progenitor cells.
Blood
75:2292,
1990[Abstract/Free Full Text]
35.
Caux C,
Favre C,
Saeland S,
Duvert V,
Durand I,
Mannoni P,
Banchereau J:
Potentiation of early hematopoiesis by tumor necrosis factor- is followed by inhibition of granulopoietic differentiation and proliferation.
Blood
78:635,
1991[Abstract/Free Full Text]
36.
Vallé A,
Zuber CE,
Defrance T,
Djossou O,
de Rie M,
Banchereau J:
Activation of human B lymphocytes through CD40 and interleukin 4.
Eur J Immunol
19:1463,
1989[Medline]
[Order article via Infotrieve]
37.
Defrance T,
Vanbervliet B,
Brière F,
Durand I,
Rousset F,
Banchereau J:
Interleukin 10 and transforming growth factor  cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A.
J Exp Med
175:671,
1992[Abstract/Free Full Text]
38.
Sallusto F,
Cella M,
Danieli C,
Lanzavecchia A:
Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Down-regulation by cytokines and bacterial products.
J Exp Med
182:389,
1995[Abstract/Free Full Text]
39.
Caux C,
Vanbervliet B,
Massacrier C,
Azuma M,
Okumura K,
Lanier LL,
Banchereau B:
B70/B7-2 is identical to CD86 and is the major functional ligand for CD28 expressed on human dendritic cells.
J Exp Med
180:1841,
1994[Abstract/Free Full Text]
40.
Caux C,
Massacrier C,
Vanbervliet B,
Barthélémy C,
Liu YJ,
Banchereau J:
Interleukin-10 inhibits T cell alloreaction induced by human dendritic cells.
Int Immunol
6:1177,
1994[Abstract/Free Full Text]
41.
Dubois B,
Vanbervliet B,
Fayette J,
Massacrier C,
van Kooten C,
Brière F,
Banchereau J,
Caux C:
Dendritic cells enhance growth and differentiation of CD40-activated B lymphocytes.
J Exp Med
185:941,
1997[Abstract/Free Full Text]
42.
Defrance T,
Vanbervliet B,
Pène J,
Banchereau J:
Human recombinant IL-4 induces activated B lymphocytes to produce IgG and IgM.
J Immunol
141:2000,
1988[Abstract]
43.
Caux C,
Massacrier C,
Vanbervliet B,
Dubois B,
van Kooten C,
Durand I,
Banchereau J:
Activation of human dendritic cells through CD40 cross-linking.
J Exp Med
180:1263,
1994[Abstract/Free Full Text]
44.
Sallusto F,
Lanzavecchia A:
Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha.
J Exp Med
179:1109,
1994[Abstract/Free Full Text]
45.
Steinman RM,
Swanson J:
The endocytic activity of dendritic cells.
J Exp Med
182:283,
1995[Free Full Text]
46.
Hoefakker S,
Van't Erve EHM,
Deen C,
Van den Eertwegh A,
Boersma WJA,
Notten WRS,
Claassen E:
Immunohistochemical detection of co-localizing cytokine and antibody producing cells in the extrafollicular area of human palatine tonsils.
Clin Exp Immunol
93:223,
1993[Medline]
[Order article via Infotrieve]
47.
Bogen SA,
Fogelman I,
Abbas AK:
Analysis of IL-2, IL-4, and IFN- -producing cells in situ during immune responses to protein antigens.
J Immunol
150:4197,
1993[Abstract]
48.
Van den Eertwegh AJM,
Noelle RJ,
Roy M,
Shepherd DM,
Aruffo A,
Ledbetter JA,
Bocrsma WJA,
Claassen E:
In vivo CD40-gp39 interactions are essential for thymus dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions.
J Exp Med
178:1555,
1993[Abstract/Free Full Text]
49.
Grabstein KH,
Maliszewski CR,
Shanebeck K,
Sato TA,
Sprigg MK,
Fanslow WC,
Armitage RJ:
The regulation of T cell-dependent antibody formation in vitro by CD40 ligand and IL-2.
J Immunol
150:3141,
1993[Abstract]
50.
Forman MS,
Puré E:
T-independent and T-dependent B lymphoblasts: Helper T cells prime for interleukin 2-induced growth and secretion of immunoglobulins that utilize downstream heavy chains.
J Exp Med
173:687,
1991[Abstract/Free Full Text]
51.
Croft M,
Swain SL:
Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL4 to drive differentiation to secretion of T helper 2-type cytokines.
J Immunol
154:4269,
1995[Abstract]
52.
Sullivan S,
Bergstresser PR,
Tigelaar RE,
Streilein JW:
Induction and regulation of contact hypersensitivity by resident bone marrow derived, dendritic epidermal cells: Langerhans cells and Thy-1+ epidermal cells.
J Immunol
137:2460,
1986[Abstract]
53.
Hsu FJ,
Benike C,
Fagnoni F,
Liles TM,
Czerwinski D,
Taidi B,
Engleman EG,
Levy R:
Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells.
Nat Med
2:52,
1996[Medline]
[Order article via Infotrieve]
54.
Mukherji B,
Chakraborty NG,
Yamasaki S,
Okino T,
Yamase H,
Sporn JR,
Kurtzman SK,
Ergin MT,
Ozols J,
Meehan J,
Mauri F:
Induction of antigen-specific cytolytic T cells in situ in human melanoma by immunization with synthetic peptide-pulsed autologous antigen presenting cells.
Proc Natl Acad Sci USA
92:8078,
1995[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
C. H. Tripp, F. Sparber, I. F. Hermans, N. Romani, and P. Stoitzner
Glycolipids Injected into the Skin Are Presented to NKT Cells in the Draining Lymph Node Independently of Migratory Skin Dendritic Cells
J. Immunol.,
June 15, 2009;
182(12):
7644 - 7654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Haniffa, F. Ginhoux, X.-N. Wang, V. Bigley, M. Abel, I. Dimmick, S. Bullock, M. Grisotto, T. Booth, P. Taub, et al.
Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation
J. Exp. Med.,
February 16, 2009;
206(2):
371 - 385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A. Stephens, E. Nikoopour, B. J. Rider, M. Leon-Ponte, T. A. Chau, S. Mikolajczak, P. Chaturvedi, E. Lee-Chan, R. A. Flavell, S. M. M. Haeryfar, et al.
Dendritic Cell Differentiation Induced by a Self-Peptide Derived from Apolipoprotein E
J. Immunol.,
November 15, 2008;
181(10):
6859 - 6871.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. V. Borderia, B. M. Hartmann, A. Fernandez-Sesma, T. M. Moran, and S. C. Sealfon
Antiviral-Activated Dendritic Cells: A Paracrine-Induced Response State
J. Immunol.,
November 15, 2008;
181(10):
6872 - 6881.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. A. M. Santegoets, H. J. Bontkes, A. G. M. Stam, F. Bhoelan, J. J. Ruizendaal, A. J. M. van den Eertwegh, E. Hooijberg, R. J. Scheper, and T. D. de Gruijl
Inducing Antitumor T Cell Immunity: Comparative Functional Analysis of Interstitial Versus Langerhans Dendritic Cells in a Human Cell Line Model
J. Immunol.,
April 1, 2008;
180(7):
4540 - 4549.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-P. Li, S. Paczesny, E. Lauret, S. Poirault, P. Bordigoni, F. Mekhloufi, O. Hequet, Y. Bertrand, J.-P. Ou-Yang, J.-F. Stoltz, et al.
Human Mesenchymal Stem Cells License Adult CD34+ Hemopoietic Progenitor Cells to Differentiate into Regulatory Dendritic Cells through Activation of the Notch Pathway
J. Immunol.,
February 1, 2008;
180(3):
1598 - 1608.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Iwamoto, S.-i. Iwai, K. Tsujiyama, C. Kurahashi, K. Takeshita, M. Naoe, A. Masunaga, Y. Ogawa, K. Oguchi, and A. Miyazaki
TNF-{alpha} Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses
J. Immunol.,
August 1, 2007;
179(3):
1449 - 1457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Gogolak, B. Rethi, I. Szatmari, A. Lanyi, B. Dezso, L. Nagy, and E. Rajnavolgyi
Differentiation of CD1a- and CD1a+ monocyte-derived dendritic cells is biased by lipid environment and PPAR{gamma}
Blood,
January 15, 2007;
109(2):
643 - 652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. L. Zhang, S. K. Malek, T. M. Blasick, J. R. Pennington, K. K. Masker, M. Lun, and S. Potdar
C4d Positivity Is Often Associated with Acute Cellular Rejection in Renal Transplant Biopsies Following Campath-1H (Alemtuzumab) Induction
Ann. Clin. Lab. Sci.,
January 1, 2007;
37(2):
121 - 126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. A. M. Santegoets, A. J. Masterson, P. C. van der Sluis, S. M. Lougheed, D. M. Fluitsma, A. J. M. van den Eertwegh, H. M. Pinedo, R. J. Scheper, and T. D. de Gruijl
A CD34+ human cell line model of myeloid dendritic cell differentiation: evidence for a CD14+CD11b+ Langerhans cell precursor
J. Leukoc. Biol.,
December 1, 2006;
80(6):
1337 - 1344.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Donaghy, J. Wilkinson, and A. L. Cunningham
HIV interactions with dendritic cells: has our focus been too narrow?
J. Leukoc. Biol.,
November 1, 2006;
80(5):
1001 - 1012.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Klinke II
An age-structured model of dendritic cell trafficking in the lung.
Am J Physiol Lung Cell Mol Physiol,
November 1, 2006;
291(5):
L1038 - L1049.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Pichavant, S. Taront, P. Jeannin, L. Breuilh, A.-S. Charbonnier, C. Spriet, C. Fourneau, N. Corvaia, L. Heliot, A. Brichet, et al.
Impact of Bronchial Epithelium on Dendritic Cell Migration and Function: Modulation by the Bacterial Motif KpOmpA
J. Immunol.,
November 1, 2006;
177(9):
5912 - 5919.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Schott
Immunesurveillance by dendritic cells: potential implication for immunotherapy of endocrine cancers.
Endocr. Relat. Cancer,
September 1, 2006;
13(3):
779 - 795.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Nauta, A. B. Kruisselbrink, E. Lurvink, R. Willemze, and W. E. Fibbe
Mesenchymal Stem Cells Inhibit Generation and Function of Both CD34+-Derived and Monocyte-Derived Dendritic Cells
J. Immunol.,
August 15, 2006;
177(4):
2080 - 2087.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.W. Cutler and R. Jotwani
Dendritic Cells at the Oral Mucosal Interface
Journal of Dental Research,
August 1, 2006;
85(8):
678 - 689.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Bechetoille, V. Andre, J. Valladeau, E. Perrier, and C. Dezutter-Dambuyant
Mixed Langerhans cell and interstitial/dermal dendritic cell subsets emanating from monocytes in Th2-mediated inflammatory conditions respond differently to proinflammatory stimuli
J. Leukoc. Biol.,
July 1, 2006;
80(1):
45 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Abbasian, D. Mahmud, N. Mahmud, S. Chunduri, H. Araki, P. Reddy, R. Hoffman, M. Arpinati, J. L. M. Ferrara, and D. Rondelli
Allogeneic T cells induce rapid CD34+ cell differentiation into CD11c+CD86+ cells with direct and indirect antigen-presenting function
Blood,
July 1, 2006;
108(1):
203 - 208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Holl, M. Peressin, S. Schmidt, T. Decoville, S. Zolla-Pazner, A.-M. Aubertin, and C. Moog
Efficient inhibition of HIV-1 replication in human immature monocyte-derived dendritic cells by purified anti-HIV-1 IgG without induction of maturation
Blood,
June 1, 2006;
107(11):
4466 - 4474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Yuan, J.-B. Latouche, J. Hodges, A. N. Houghton, G. Heller, M. Sadelain, I. Riviere, and J. W. Young
Langerhans-Type Dendritic Cells Genetically Modified to Express Full-Length Antigen Optimally Stimulate CTLs in a CD4-Dependent Manner
J. Immunol.,
February 15, 2006;
176(4):
2357 - 2365.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hofer, K. Pfeil, H. Niederegger, S. Ebner, V. A. Nguyen, E. Kremmer, M. Auffinger, S. Neyer, C. Furhapter, and C. Heufler
Dendritic cells regulate T-cell deattachment through the integrin-interacting protein CYTIP
Blood,
February 1, 2006;
107(3):
1003 - 1009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Vermaelen and R. Pauwels
Pulmonary Dendritic Cells
Am. J. Respir. Crit. Care Med.,
September 1, 2005;
172(5):
530 - 551.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rossi and J. W. Young
Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity
J. Immunol.,
August 1, 2005;
175(3):
1373 - 1381.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. D. Cravens, M. W. Melkus, A. Padgett-Thomas, M. Islas-Ohlmayer, M. del P. Martin, and J. V. Garcia
Development and Activation of Human Dendritic Cells In Vivo in a Xenograft Model of Human Hematopoiesis
Stem Cells,
February 1, 2005;
23(2):
264 - 278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. McKenna, A.-S. Beignon, and N. Bhardwaj
Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity
J. Virol.,
January 1, 2005;
79(1):
17 - 27.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Platzer, A. Jorgl, S. Taschner, B. Hocher, and H. Strobl
RelB regulates human dendritic cell subset development by promoting monocyte intermediates
Blood,
December 1, 2004;
104(12):
3655 - 3663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. de Repentigny, D. Lewandowski, and P. Jolicoeur
Immunopathogenesis of Oropharyngeal Candidiasis in Human Immunodeficiency Virus Infection
Clin. Microbiol. Rev.,
October 1, 2004;
17(4):
729 - 759.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Do, V. L. Hegde, P. S. Nagarkatti, and M. Nagarkatti
Bryostatin-1 Enhances the Maturation and Antigen-Presenting Ability of Murine and Human Dendritic Cells
Cancer Res.,
September 15, 2004;
64(18):
6756 - 6765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Encabo, P. Solves, E. Mateu, P. Sepulveda, F. Carbonell-Uberos, and M. D. Minana
Selective Generation of Different Dendritic Cell Precursors from CD34+ Cells by Interleukin-6 and Interleukin-3
Stem Cells,
September 1, 2004;
22(5):
725 - 740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ratzinger, J. Baggers, M. A. de Cos, J. Yuan, T. Dao, J. L. Reagan, C. Munz, G. Heller, and J. W. Young
Mature Human Langerhans Cells Derived from CD34+ Hematopoietic Progenitors Stimulate Greater Cytolytic T Lymphocyte Activity in the Absence of Bioactive IL-12p70, by Either Single Peptide Presentation or Cross-Priming, Than Do Dermal-Interstitial or Monocyte-Derived Dendritic Cells
J. Immunol.,
August 15, 2004;
173(4):
2780 - 2791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Rial, D. Lens, L. Betancor, H. Benkiel, J. S. Silva, and J. A. Chabalgoity
Intranasal Immunization with a Colloid-Formulated Bacterial Extract Induces an Acute Inflammatory Response in the Lungs and Elicits Specific Immune Responses
Infect. Immun.,
May 1, 2004;
72(5):
2679 - 2688.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Chen, S. Antonenko, J. M. Sederstrom, X. Liang, A. S. H. Chan, H. Kanzler, B. Blom, B. R. Blazar, and Y.-J. Liu
Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors
Blood,
April 1, 2004;
103(7):
2547 - 2553.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. J. Megjugorac, H. A. Young, S. B. Amrute, S. L. Olshalsky, and P. Fitzgerald-Bocarsly
Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells
J. Leukoc. Biol.,
March 1, 2004;
75(3):
504 - 514.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Monaco and E. Paleolog
Nuclear factor {kappa}B: a potential therapeutic target in atherosclerosis and thrombosis
Cardiovasc Res,
March 1, 2004;
61(4):
671 - 682.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. K. Palucka, J. Gatlin, J. P. Blanck, M. W. Melkus, S. Clayton, H. Ueno, E. T. Kraus, P. Cravens, L. Bennett, A. Padgett-Thomas, et al.
Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors
Blood,
November 1, 2003;
102(9):
3302 - 3310.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Woltman and C. van Kooten
Functional modulation of dendritic cells to suppress adaptive immune responses
J. Leukoc. Biol.,
April 1, 2003;
73(4):
428 - 441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Ratzinger, J. L. Reagan, G. Heller, K. J. Busam, and J. W. Young
Differential CD52 expression by distinct myeloid dendritic cell subsets: implications for alemtuzumab activity at the level of antigen presentation in allogeneic graft-host interactions in transplantation
Blood,
February 15, 2003;
101(4):
1422 - 1429.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fiorini, W. Vermi, F. Facchetti, D. Moratto, G. Alessandri, L. Notarangelo, A. Caruso, P. Grigolato, A. G. Ugazio, L. D. Notarangelo, et al.
Defective migration of monocyte-derived dendritic cells in LAD-1 immunodeficiency
J. Leukoc. Biol.,
October 1, 2002;
72(4):
650 - 656.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Ahn, Y. Lee, C. Jeon, S.-J. Lee, B.-H. Lee, K. D. Choi, and Y.-S. Bae
Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis
Blood,
August 13, 2002;
100(5):
1742 - 1754.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mohty, D. Isnardon, A. Charbonnier, M. Lafage-Pochitaloff, M. Merlin, D. Sainty, D. Olive, and B. Gaugler
Generation of potent Th1 responses from patients with lymphoid malignancies after differentiation of B lymphocytes into dendritic-like cells
Int. Immunol.,
July 1, 2002;
14(7):
741 - 750.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Masterson, C. C. Sombroek, T. D. de Gruijl, Y. M. F. Graus, H. J. J. van der Vliet, S. M. Lougheed, A. J. M. van den Eertwegh, H. M. Pinedo, and R. J. Scheper
MUTZ-3, a human cell line model for the cytokine-induced differentiation of dendritic cells from CD34+ precursors
Blood,
June 28, 2002;
100(2):
701 - 703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Woltman, C. Massacrier, J. W. de Fijter, C. Caux, and C. van Kooten
Corticosteroids Prevent Generation of CD34+-Derived Dermal Dendritic Cells But Do Not Inhibit Langerhans Cell Development
J. Immunol.,
June 15, 2002;
168(12):
6181 - 6188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-T. Wu and S. T. Hwang
CXCR5-Transduced Bone Marrow-Derived Dendritic Cells Traffic to B Cell Zones of Lymph Nodes and Modify Antigen-Specific Immune Responses
J. Immunol.,
May 15, 2002;
168(10):
5096 - 5102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Page, S. Lebecque, and P. Miossec
Anatomic Localization of Immature and Mature Dendritic Cells in an Ectopic Lymphoid Organ: Correlation with Selective Chemokine Expression in Rheumatoid Synovium
J. Immunol.,
May 15, 2002;
168(10):
5333 - 5341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. F. Lipscomb and B. J. Masten
Dendritic Cells: Immune Regulators in Health and Disease
Physiol Rev,
January 1, 2002;
82(1):
97 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. C. Heystek, C. Moulon, A. M. Woltman, P. Garonne, and C. van Kooten
Human Immature Dendritic Cells Efficiently Bind and Take up Secretory IgA Without the Induction of Maturation
J. Immunol.,
January 1, 2002;
168(1):
102 - 107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-C. Dieu-Nosjean, C. Massacrier, B. Vanbervliet, W.-H. Fridman, and C. Caux
IL-10 Induces CCR6 Expression During Langerhans Cell Development While IL-4 and IFN-{gamma} Suppress It
J. Immunol.,
November 15, 2001;
167(10):
5594 - 5602.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jinquan, L. Anting, H. H. Jacobi, C. Glue, C. Jing, L. P. Ryder, H. O. Madsen, A. Svejgaard, P. S. Skov, H.-J. Malling, et al.
CXCR3 Expression on CD34+ Hemopoietic Progenitors Induced by Granulocyte-Macrophage Colony-Stimulating Factor: II. Signaling Pathways Involved
J. Immunol.,
October 15, 2001;
167(8):
4405 - 4413.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Banchereau, A. K. Palucka, M. Dhodapkar, S. Burkeholder, N. Taquet, A. Rolland, S. Taquet, S. Coquery, K. M. Wittkowski, N. Bhardwaj, et al.
Immune and Clinical Responses in Patients with Metastatic Melanoma to CD34+ Progenitor-derived Dendritic Cell Vaccine
Cancer Res.,
September 1, 2001;
61(17):
6451 - 6458.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Ohishi, B. Varnum-Finney, R. E. Serda, C. Anasetti, and I. D. Bernstein
The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells
Blood,
September 1, 2001;
98(5):
1402 - 1407.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. W. Cutler, R. Jotwani, and B. Pulendran
Dendritic Cells: Immune Saviors or Achilles' Heel?
Infect. Immun.,
August 1, 2001;
69(8):
4703 - 4708.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Santiago-Schwarz, P. Anand, S. Liu, and S. E. Carsons
Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses
J. Immunol.,
August 1, 2001;
167(3):
1758 - 1768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Woltman, J. W. de Fijter, S. W. A. Kamerling, S. W. van der Kooij, L. C. Paul, M. R. Daha, and C. van Kooten
Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages
Blood,
July 1, 2001;
98(1):
174 - 180.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Suzuki, Y. Tsutsumi, M. Nakagawa, H. Suzuki, K. Matsushita, M. Beppu, H. Aoki, Y. Ichikawa, and Y. Mizushima
Osteoclast-like cells in an in vitro model of bone destruction by rheumatoid synovium
Rheumatology,
June 1, 2001;
40(6):
673 - 682.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. A. Kingsbury, L. A. Feeney, Y. Nong, S. A Calandra, C. J. Murphy, J. M. Corcoran, Y. Wang, M. R. Prabhu Das, S. J. Busfield, C. C. Fraser, et al.
Cloning, Expression, and Function of BLAME, a Novel Member of the CD2 Family
J. Immunol.,
May 1, 2001;
166(9):
5675 - 5680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. MacAry, M. Lindsay, M. A. Scott, J. I. O. Craig, J. P. Luzio, and P. J. Lehner
Mobilization of MHC class I molecules from late endosomes to the cell surface following activation of CD34-derived human Langerhans cells
PNAS,
March 27, 2001;
98(7):
3982 - 3987.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Banchereau, B. Pulendran, R. Steinman, and K. Palucka
Will the Making of Plasmacytoid Dendritic Cells In Vitro Help Unravel Their Mysteries?
J. Exp. Med.,
December 18, 2000;
192(12):
F39 - F44.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Blom, S. Ho, S. Antonenko, and Y.-J. Liu
Generation of Interferon {{alpha}}-producing Predendritic Cell (Pre-DC)2 from Human CD34+ Hematopoietic Stem Cells
J. Exp. Med.,
December 18, 2000;
192(12):
1785 - 1796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Canque, S. Camus, A. Dalloul, E. Kahn, M. Yagello, C. Dezutter-Dambuyant, D. Schmitt, C. Schmitt, and J. C. Gluckman
Characterization of dendritic cell differentiation pathways from cord blood CD34+CD7+CD45RA+ hematopoietic progenitor cells
Blood,
December 1, 2000;
96(12):
3748 - 3756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Spanbroek, M. Hildner, D. Steinhilber, N. Fusenig, K. Yoneda, O. R. B. Samuelsson, and A. J.R. Habenicht
5-lipoxygenase expression in dendritic cells generated from CD34+ hematopoietic progenitors and in lymphoid organs
Blood,
December 1, 2000;
96(12):
3857 - 3865.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. AUSTYN
Antigen-presenting Cells . Experimental and Clinical Studies of Dendritic Cells
Am. J. Respir. Crit. Care Med.,
October 1, 2000;
162(4):
S146 - 150.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-C. Dieu-Nosjean, C. Massacrier, B. Homey, B. Vanbervliet, J.-J. Pin, A. Vicari, S. Lebecque, C. Dezutter-Dambuyant, D. Schmitt, A. Zlotnik, et al.
Macrophage Inflammatory Protein 3{alpha} Is Expressed at Inflamed Epithelial Surfaces and Is the Most Potent Chemokine Known in Attracting Langerhans Cell Precursors
J. Exp. Med.,
September 5, 2000;
192(5):
705 - 718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Jinquan, S. Quan, H. H. Jacobi, C. Jing, A. Millner, B. Jensen, H. O. Madsen, L. P. Ryder, A. Svejgaard, H.-J. Malling, et al.
CXC chemokine receptor 3 expression on CD34+ hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor: chemotaxis and adhesion induced by its ligands, interferon gamma -inducible protein 10 and monokine induced by interferon gamma
Blood,
August 15, 2000;
96(4):
1230 - 1238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Maraskovsky, E. Daro, E. Roux, M. Teepe, C. R. Maliszewski, J. Hoek, D. Caron, M. E. Lebsack, and H. J. McKenna
In vivo generation of human dendritic cell subsets by Flt3 ligand
Blood,
August 1, 2000;
96(3):
878 - 884.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Daro, B. Pulendran, K. Brasel, M. Teepe, D. Pettit, D. H. Lynch, D. Vremec, L. Robb, K. Shortman, H. J. McKenna, et al.
Polyethylene Glycol-Modified GM-CSF Expands CD11bhighCD11chigh But Not CD11blowCD11chigh Murine Dendritic Cells In Vivo: A Comparative Analysis with Flt3 Ligand
J. Immunol.,
July 1, 2000;
165(1):
49 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. E. Schneeberger, Q. Vu, B. W. LeBlanc, and C. M. Doerschuk
The Accumulation of Dendritic Cells in the Lung Is Impaired in CD18-/- But Not in ICAM-1-/- Mutant Mice
J. Immunol.,
March 1, 2000;
164(5):
2472 - 2478.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Johansson, S. Ingvarsson, P. Bjorck, and C. A. K. Borrebaeck
Human Interdigitating Dendritic Cells Induce Isotype Switching and IL-13-Dependent IgM Production in CD40-Activated Naive B Cells
J. Immunol.,
February 15, 2000;
164(4):
1847 - 1854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Ferrero, K. Vettoretto, A. Bondanza, A. Villa, M. Resnati, A. Poggi, and M. R. Zocchi
uPA/uPAR System Is Active in Immature Dendritic Cells Derived from CD14+CD34+ Precursors and Is Down-Regulated upon Maturation
J. Immunol.,
January 15, 2000;
164(2):
712 - 718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Gutiérrez-Rodríguez, E. Reyes-Maldonado, and H. Mayani
Characterization of the Adherent Cells Developed in Dexter-Type Long-Term Cultures from Human Umbilical Cord Blood
Stem Cells,
January 1, 2000;
18(1):
46 - 52.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. Brenner, C. Rossig, U. Sili, J. W. Young, and E. Goulmy
Transfusion Medicine: New Clinical Applications of Cellular Immunotherapy
Hematology,
January 1, 2000;
2000(1):
356 - 375.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Galy, I. Christopherson, G. Ferlazzo, G. Liu, H. Spits, and K. Georgopoulos
Distinct signals control the hematopoiesis of lymphoid-related dendritic cells
Blood,
January 1, 2000;
95(1):
128 - 137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Wilson, L. C. Heffler, J. Charo, A. Scheynius, M.-T. Bejarano, and H.-G. Ljunggren
Targeting of Human Dendritic Cells by Autologous NK Cells
J. Immunol.,
December 15, 1999;
163(12):
6365 - 6370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Cochand, P. Isler, F. Songeon, and L. P. Nicod
Human Lung Dendritic Cells Have an Immature Phenotype with Efficient Mannose Receptors
Am. J. Respir. Cell Mol. Biol.,
November 1, 1999;
21(5):
547 - 554.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Jaksits, E. Kriehuber, A. S. Charbonnier, K. Rappersberger, G. Stingl, and D. Maurer
CD34+ Cell-Derived CD14+ Precursor Cells Develop into Langerhans Cells in a TGF-{beta}1-Dependent Manner
J. Immunol.,
November 1, 1999;
163(9):
4869 - 4877.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. E. M. Bates, N. Fournier, E. Garcia, J. Valladeau, I. Durand, J.-J. Pin, S. M. Zurawski, S. Patel, J. S. Abrams, S. Lebecque, et al.
APCs Express DCIR, a Novel C-Type Lectin Surface Receptor Containing an Immunoreceptor Tyrosine-Based Inhibitory Motif
J. Immunol.,
August 15, 1999;
163(4):
1973 - 1983.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Tiefenthaler, R. Marksteiner, S. Neyer, F. Koch, S. Hofer, G. Schuler, M. Nussenzweig, R. Schneider, and C. Heufler
M1204, a Novel 2',5' Oligoadenylate Synthetase with a Ubiquitin-Like Extension, Is Induced During Maturation of Murine Dendritic Cells
J. Immunol.,
July 15, 1999;
163(2):
760 - 765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Linehan, L. Martinez-Pomares, P. D. Stahl, and S. Gordon
Mannose Receptor and Its Putative Ligands in Normal Murine Lymphoid and Nonlymphoid Organs: In Situ Expression of Mannose Receptor by Selected Macrophages, Endothelial Cells, Perivascular Microglia, and Mesangial Cells, but not Dendritic Cells
J. Exp. Med.,
June 21, 1999;
189(12):
1961 - 1972.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Canque, Y. Bakri, S. Camus, M. Yagello, A. Benjouad, and J. C. Gluckman
The Susceptibility to X4 and R5 Human Immunodeficiency Virus-1 Strains of Dendritic Cells Derived In Vitro From CD34+ Hematopoietic Progenitor Cells Is Primarily Determined by Their Maturation Stage
Blood,
June 1, 1999;
93(11):
3866 - 3875.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ogata, Y. Zhang, Y. Wang, M. Itakura, Y.-y. Zhang, A. Harada, S.-i. Hashimoto, and K. Matsushima
Chemotactic Response Toward Chemokines and Its Regulation by Transforming Growth Factor-{beta}1 of Murine Bone Marrow Hematopoietic Progenitor Cell-Derived Different Subset of Dendritic Cells
Blood,
May 15, 1999;
93(10):
3225 - 3232.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Geissmann, P. Revy, A. Regnault, Y. Lepelletier, M. Dy, N. Brousse, S. Amigorena, O. Hermine, and A. Durandy
TGF-{beta}1 Prevents the Noncognate Maturation of Human Dendritic Langerhans Cells
J. Immunol.,
April 15, 1999;
162(8):
4567 - 4575.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Raje, J. Gong, D. Chauhan, G. Teoh, D. Avigan, Z. Wu, D. Chen, S. P. Treon, I. J. Webb, D. W. Kufe, et al.
Bone Marrow and Peripheral Blood Dendritic Cells From Patients With Multiple Myeloma Are Phenotypically and Functionally Normal Despite the Detection of Kaposi's Sarcoma Herpesvirus Gene Sequences
Blood,
March 1, 1999;
93(5):
1487 - 1495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, Y.-y. Zhang, M. Ogata, P. Chen, A. Harada, S.-i. Hashimoto, and K. Matsushima
Transforming Growth Factor-beta 1 Polarizes Murine Hematopoietic Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells Through a Monocyte/Macrophage Differentiation Pathway
Blood,
February 15, 1999;
93(4):
1208 - 1220.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Stumbles, J. A. Thomas, C. L. Pimm, P. T. Lee, T. J. Venaille, S. Proksch, and P. G. Holt
Resting Respiratory Tract Dendritic Cells Preferentially Stimulate T Helper Cell Type 2 (Th2) Responses and Require Obligatory Cytokine Signals for Induction of Th1 Immunity
J. Exp. Med.,
December 7, 1998;
188(11):
2019 - 2031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Cavanagh, R. J. Saal, K. L. Grimmett, and R. Thomas
Proliferation in Monocyte-Derived Dendritic Cell Cultures Is Caused by Progenitor Cells Capable of Myeloid Differentiation
Blood,
September 1, 1998;
92(5):
1598 - 1607.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Santiago-Schwarz, M. McCarthy, J. Tucci, and S. E. Carsons
Neutralization of Tumor Necrosis Factor Activity Shortly After the Onset of Dendritic Cell Hematopoiesis Reveals a Novel Mechanism for the Selective Expansion of the CD14-Dependent Dendritic Cell Pathway
Blood,
August 1, 1998;
92(3):
745 - 755.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-C. Dieu, B. Vanbervliet, A. Vicari, J.-M. Bridon, E. Oldham, S. Ait-Yahia, F. Briere, A. Zlotnik, S. Lebecque, and C. Caux
Selective Recruitment of Immature and Mature Dendritic Cells by Distinct Chemokines Expressed in Different Anatomic Sites
J. Exp. Med.,
July 20, 1998;
188(2):
373 - 386.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, A. Harada, J.-b. Wang, Y.-y. Zhang, S.-i. Hashimoto, M. Naito, and K. Matsushima
Bifurcated Dendritic Cell Differentiation In Vitro From Murine Lineage Phenotype-Negative c-kit+ Bone Marrow Hematopoietic Progenitor Cells
Blood,
July 1, 1998;
92(1):
118 - 128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Canque, S. Camus, M. Yagello, and J. C. Gluckman
Special Susceptibility to Apoptosis of CD1a+ Dendritic Cell Precursors Differentiating from Cord Blood CD34+ Progenitors
Stem Cells,
May 1, 1998;
16(3):
218 - 228.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
B. de Saint-Vis, I. Fugier-Vivier, C. Massacrier, C. Gaillard, B. Vanbervliet, S. Ait-Yahia, J. Banchereau, Y.-J. Liu, S. Lebecque, and C. Caux
The Cytokine Profile Expressed by Human Dendritic Cells Is Dependent on Cell Subtype and Mode of Activation
J. Immunol.,
February 15, 1998;
160(4):
1666 - 1676.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Schuler and R.M. Steinman
Dendritic Cells as Adjuvants for Immune-mediated Resistance to Tumors
J. Exp. Med.,
October 20, 1997;
186(8):
1183 - 1187.
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract