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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Manz, M. G. Articles by Akashi, K. Search for Related Content PubMed PubMed Citation Articles by Manz, M. G. Articles by Akashi, K. Related Collections Immunobiology Plenary Papers Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2001, Vol. 97, No. 11, pp. 3333-3341 PLENARY PAPER Dendritic cell potentials of early lymphoid and myeloid progenitors Markus G. Manz, David Traver, Toshihiro Miyamoto, Irving L. Weissman, and Koichi Akashi From the Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA; and the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA.     Abstract Top Abstract Introduction Materials and methods Results Discussion References It has been proposed that there are at least 2 classes of dendritic cells (DCs), CD8+ DCs derived from the lymphoid lineage and CD8 DCs derived from the myeloid lineage. Here, the abilities of lymphoid- and myeloid-restricted progenitors to generate DCs are compared, and their overall contributions to the DC compartment are evaluated. It has previously been shown that primitive myeloid-committed progenitors (common myeloid progenitors [CMPs]) are efficient precursors of both CD8+ and CD8 DCs in vivo. Here it is shown that the earliest lymphoid-committed progenitors (common lymphoid progenitors [CLPs]) and CMPs and their progeny granulocyte-macrophage progenitors (GMPs) can give rise to functional DCs in vitro and in vivo. CLPs are more efficient in generating DCs than their T-lineage descendants, the early thymocyte progenitors and pro-T cells, and CMPs are more efficient DC precursors than the descendant GMPs, whereas pro-B cells and megakaryocyte-erythrocyte progenitors are incapable of generating DCs. Thus, DC developmental potential is preserved during T- but not B-lymphoid differentiation from CLP and during granulocyte-macrophage but not megakaryocyte-erythrocyte development from CMP. In vivo reconstitution experiments show that CLPs and CMPs can reconstitute CD8+ and CD8 DCs with similar efficiency on a per cell basis. However, CMPs are 10-fold more numerous than CLPs, suggesting that at steady state, CLPs provide only a minority of splenic DCs and approximately half the DCs in thymus, whereas most DCs, including CD8+ and CD8 subtypes, are of myeloid origin. (Blood. 2001;97:3333-3341) © 2001 by The American Society of Hematology.     Introduction Top Abstract Introduction Materials and methods Results Discussion References Dendritic cells (DCs) are key regulators of the immune system. They are capable of stimulating lymphocytes to generate potent cell-mediated and humoral immune responses to foreign antigens, and can educate T cells to tolerate self-antigens.1-5 This variety of DC functions may result from the heterogeneity of DC subsets. It has been reported that there are at least 2 phenotypically different DC subsets in miceCD8+CD11b and CD8CD11b+ DC.6 The CD8+CD11b DCs have been considered to be related to the T-lymphoid lineage because early thymocyte progenitors (TP) (CD4loCD44+ CD25c-Kit+) and thymic pro-T cells (CD44+ CD25+c-Kit+) contain precursors capable of differentiating into DCs of this phenotype when transplanted and because most thymic DCs are CD8+CD11b.7,8 TP and pro-T cells reportedly give rise to DCs in vitro without the need of granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-4,9 both of which are important for the in vitro development of myeloid-derived DCs.10-14 One approach to infer cell lineage relationships is to examine cell subsets in mutant mice. Mice deficient in the transcripion factors RelB,15 PU.1,16 and Ikaros17 lack only CD8 DCs supporting, but not directly demonstrating, the model for different developmental pathways of CD8+ and CD8 DCs. In contrast, other mutants give results inconsistent with a tight relation of T cells and DCs through a common progenitor in the thymus. Two recent studies show a developmental dissociation of CD8+ DCs and T cells in c-Kitc18 and Notch1/19 mice. Both mutant animals are completely deficient in T cells but show normal percentages of CD8+ DCs in thymus and spleen. Although the complete absence of TP was not formally proven in these mice, TP may not be a required stage for thymic DC development. Furthermore, the TP population is likely heterogeneous, containing precursors for both thymocytes and some myelomonocytic cells.7,20 Thus, a genetic approach to dissect lineage relationships between myeloid and lymphoid progenitors and the 2 phenotypically distinct DC subsets is inconclusive.21 We believe the most direct way to identify lineage relationships is to isolate clonogenic precursors to purity and to test their full developmental capacity. We have recently isolated clonogenic common lymphoid progenitors (CLPs)22 and clonogenic common myeloid progenitors (CMPs) and their downstream granulocyte-macrophage (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs)23 from mouse bone marrow. Differentiation potentials of CLP, CMP, and GMP are restricted to either lymphoid lineages (T, B, natural killer [NK] cells) or myeloid lineages. We have previously demonstrated that CMPs are highly efficient precursors of both CD8+ and CD8 DCs.24 Here, we compared the DC developmental potentials of the lymphoid precursors CLPs, TPs, pro-T cells, and pro-B cells, and the myeloid precursors CMPs, GMPs, and MEPs. We demonstrated directly that CLPs can give rise to functional DCs in vivo and in vitro with greater efficiency than downstream TPs and pro-T cells. In addition, CMPs and GMPs give rise to DCs, whereas DC differentiation activity was undetected in pro-B cells and MEP. Thus, there is a DC developmental pathway independent of myeloid differentiation, and this potential is preserved from CLP to pro-T stages but not in B-cell progenitors. We also show that these lymphoid-derived DCs include CD8+ and CD8 DCs but are likely to constitute only a minority of DCs in spleen and approximately half the DCs in thymus, whereas CMPs appear to be the major source of CD8+ and CD8 DCs throughout the body.     Materials and methods Top Abstract Introduction Materials and methods Results Discussion References Animals C57BL/Ka-Thy1.1 (CD45.1), C57BL/Ka-Thy1.1 (CD45.2), and BALB/c mice were used as described.22,23 All mice were maintained in the Stanford University Research Animal Facility in accordance with Stanford guidelines. Antibodies, cell staining, and sorting The following antibodies were used: M1/70 (anti-Mac-1, anti-CD11b), 8C5 (anti-Gr-1), 6B2 (anti-B220), KT-31 (anti-CD3), GK1.5 (anti-CD4), 53-6.7 (anti-CD8), anti-TER119, A7R34 (anti-IL-7R, CD127), 2B8 (anti-c-Kit, CD117), 3C11 (anti-c-Kit, CD117), E13-161-7 (anti-Sca-1), 19XE5 (anti-Thy-1.1), A20.1.7 (anti-CD45.1), AL1-4A2 (anti-CD45.2), NLDC145 (anti-DEC205) (Serotec, Oxford, United Kingdom), and goat anti-rat IgG (PE or Cy5-PE conjugated) (Caltag, Burlingame, CA). Antibodies purchased from Pharmingen were R6-60.2 (anti-IgM), 2.4G2 (anti-FcRII/III), RAM34 (anti-CD34), NK1.1 (anti-NK cell marker), S7 (anti-CD43), 7D4 (anti-IL2R, CD25), 1D3 (anti-CD19), AF6-120.1 (anti-IAb), HL3 (anti-CD11c), 16-10A1 (anti-CD80), GL1(anti-CD86), and 3/23 (anti-CD40) (San Diego, CA). For visualization of biotinylated antibodies, streptavidin-conjugated phycoerythrin (PE), Cy5-PE, and Texas red (Gibco, Rockville, MD) were used. CLPs, TPs, pro-T cells, pro-B cells, CMPs, GMPs, and MEPs were sorted as reported elsewhere.8,22,23,25 Thorough methodologies for staining and sorting CLPs, CMPs, GMPs, and MEPs can be found at http://www.metazoa.com UPL 2030 and UPL 2001. In brief, for CLP and the myeloid progenitors, lineage-positive (Lin+) (CD3, CD4, CD5, CD8, B220, IgM, CD19, Mac-1, Gr-1, Ter119) cells were partially removed by immunomagnetic depletion, and CLPs were sorted as lineage-negative (Lin) IL-7R+ Thy-1Sca-1lo c-Kitlo cells. Myeloid progenitors were sorted as LinSca-1c-Kit+CD34+FcRlo (CMP), LinSca-1c-Kit+ CD34+FcRhi (GMP), and LinSca-1c-Kit+CD34FcRlo (MEP) cells. TP (CD3CD8CD4loc-Kit+CD25) and pro-T cells (CD3CD8CD4 c-Kit+CD25+) were sorted after immunomagnetic c-Kit enrichment (biotinylated anti-c-Kit) (3C11 streptavidin microbeads [Miltenyi Biotec, Bergisch-Gladbach, Germany]). Pro-B cells (CD43+B220+IgMNK1.1 or CD19+CD43+IgM) were sorted after partial immunomagnetic removal of Gr.1+ and Mac-1+ cells. For all experiments, dead cells were excluded by propidium iodide staining, and appropriate isotype-matched, irrelevant control monoclonal antibodies were used to determine the level of background staining. Cells were sorted and analyzed using a highly modified dual-laser FACS (488-nm argon laser, 599-nm dye laser) (FACS Vantage; Becton Dickinson Immunocytometry Systems, Mountain View, CA). All cultured and transplanted progenitors and all cells for polymerase chain reaction (PCR) analysis were purified by sorting and resorting to obtain precise numbers of cells essentially pure for the indicated surface marker phenotype. For single-cell and limiting-dilution assays, the re-sort was performed using an automatic cell deposition unit system (Becton Dickinson). The specific number of cells sorted in each well was confirmed by visual inspection under an inverted microscope. For analysis of cultured or in vivo reconstituted cells, antibody staining was used as indicated in "Results." In vitro differentiation assay CLPs, TPs, pro-T cells, pro-B cells, and the myeloid progenitors were cultured in Iscoves modified Dulbecco medium (Gibco) supplemented with 10% fetal calf serum (FCS), 104 M 2-mercaptoethanol, sodium pyruvate, and antibiotics. Murine IL-1 (10 ng/mL), IL-3 (20 ng/mL), IL-4 (10 ng/mL), IL-7 (10 ng/mL), steel factor (SLF) (10 ng/mL), tumor necrosis factor  (TNF-) (10 ng/mL), Flt3-L (40 ng/mL), GM-CSF (10 ng/mL), and M-CSF (10 ng/mL) were used as indicated (all cytokines from R&D Systems, Minneapolis, MN). Cells were cultured in 60-well Terasaki trays (up to 103 cells/well) or in 96-well plates (up to 104 cells/well). Cluster formation was evaluated using inverted phase-contrast microscopy. To use cells in further assays, DC clusters were disrupted by adding 0.1 vol of 0.1 M EDTA and by repeated pipetting. All cultures were incubated at 37°C in a humidified chamber under 7% CO2. Lineage-reduced bone marrow-derived DCs were generated in culture as described11 using GM-CSF (10 ng/mL) with the addition of IL-4 (10 ng/mL). Mixed leukocyte reaction Graded numbers (103-104) of irradiated (25 Gy) DCs either harvested from cultures or sorted from reconstituted animals (all C57Bl/Ka) were plated in U-bottom 96-well plates together with 2 × 105 splenocytes or 1 × 105 lymph node cells of BALB/c mice in a final volume of 200 µL. Culture media consisted of RPMI 1640 and 10% FCS. No cytokines were added. Cells were cultured for 4 days and pulsed with 1 µCi 3H-thymidine per well during the last 16 hours of culture. 3H-thymidine incorporation was measured on a -plate counter (Wallac, Gaithersburg, MD). RT-PCR analysis Total RNA was extracted from 103 double-sorted CLPs taken from bone marrow, 103 double-sorted major histocompatibility complex (MHC) class II+CD11c+CD8+ and MHC class II+CD11c+CD8 cells from spleen, 103 double-sorted MHC class II+CD11c+CD8+ from thymus, and 103 double-sorted MHC class II+CD11c+ DC from day 4 of CLP culture. These RNA samples were reverse-transcribed to cDNA as described previously.23,26 cDNA was analyzed for the presence of MHC class II activator (CIITA), Epstein-Barr virus-induced molecule-1 ligand chemokine (ELC), RelB, PU.1, CD8, and CD3. PCR primer sequences and annealing temperatures used were as follows: CIITA-F, CCA GAA CTG GTT GTA GAG CC; CIITA-R, CAG CTT GCT AGG CTC CAA TT (tm, 65°C), resulting in a 500-bp PCR product27; ELC-F, GGT GCT AAT GAT GCG GAA GAC; ELC-R, AGA CAC AGG GCT CCT TCT GGT (tm, 65°C), resulting in a 250-bp PCR product28; RelB-F, GAT CCA CAT GGA ATC GAG AG; RelB-R, AGA TGT CCG ATT CAG GAT GA (tm, 60°C), resulting a 575-bp PCR product29; PU.1-F, TGG AAG GGT TTT CCC TCA CC; PU.1-R, TGC TGT CCT TCA TGT CGC CG (tm, 60°C), resulting in a 615-bp PCR product30; CD8-F, CAC GAA TAA TAA GTA CGT TCT CAC C; CD8-R, ATG TAA ATA TCA CAG GCG AAG TCC A (tm, 60°C), resulting in a 268-bp PCR product; CD3-F, GAA AGA ATC AGG CTG CTC AGA; and CD3-R, TGG AGA TGG TGA TGA CCA TCC GA (tm, 60°C), resulting in a 539-bp PCR product. The HPRT gene was also amplified as a control. PCR amplification consisted of an initial denaturation step at 94°C for 3 minutes, followed by 32 cycles at 94°C for 30 seconds, annealing for 30 seconds, and extension at 72°C for 90 seconds in each cycle. PCR products were electrophoresed on an ethidium bromide-stained 2.0% agarose gel. PCR amplification was repeated at least twice for at least 2 separately prepared cDNA samples for each experiment. In vivo reconstitution assays For reconstitution assays, purified progenitors were injected into the retro-orbital venous sinus of 8- to 12-week-old, lethally irradiated (9.5 Gy) congenic mice, which differed only at the CD45 allele, together with 2 × 105 host CD45-type whole bone marrow cells. The presence of donor-derived DCs was evaluated at different time points. DCs were isolated as described elsewere.7,31 Briefly, spleens and thymi were cut in small fragments and digested under repeated agitation for 30 minutes. at 37°C in RPMI 1640 supplemented with 10% FCS, collagenase (1 mg/mL) (Collagenase D; Boehringer Mannheim, Mannheim, Germany), and DNAse (50 µg/mL) (DNAse I from bovine pancreas grade II; Boehringer Mannheim). After organ digestion, EDTA was added at a concentration of 10 mM to disrupt DC complexes, and it was maintained in the medium throughout the subsequent procedures. Debris was removed by filtration, and red cells were osmotically lysed. Initially, DCs were enriched by gradient centrifugation using Nycodenz medium (Nycomed AS, Oslo, Norway) followed by immunomagnetic depletion of the remaining T cells, B cells, and neutrophils as described.7,31 However, using this method, we had low DC recovery rates. Therefore, we used CD11c+ selection for DC enrichment in all subsequent experiments, which resulted in high recovery rates. Single-cell suspensions were incubated for 10 minutes with mouse immunoglobulin to block Fc receptors. This was followed by 25-minute incubation with CD11c (N418) MicroBeads (Miltenyi Biotec) and positive selection over a magnetic column (MiniMACS and MidiMACS; Miltenyi Biotec) according to the manufacturer's instructions. Finally, cells were fluorescence-labeled and analyzed or sorted as indicated in "Results." To evaluate DC percentages of total cells, staining and analysis were performed after the digestion of organs without further DC enrichment.     Results Top Abstract Introduction Materials and methods Results Discussion References CLPs differentiate into DCs in vitro CLPs were sorted and cultured at 100 to 1000 cells per well in Terasaki 60-well plates containing a variety of recombinant cytokines (Table 1). Cells with cytoplasmic extensions characteristic of DC morphology were observed starting on day 1.5 of culture and formed expanding clusters ranging from 5 to more than 50 cells. Cluster size appeared to reflect DC density rather than proliferation on a single-cell basis; clusters with more than 20 cells were rarely observed in cultures started with fewer than 500 CLPs. The maximum number of cells was reached on day 4 to 5 of culture; thereafter, most cells died with approximately 10% of cells remaining on day 12 of culture. On day 4, the number of clusters containing 10 or more DCs in cultures grown from 103 CLPs was used to determine the effect of cytokines on DC differentiation and proliferation (Table 1). The highest cluster number and expansion (approximately 5-fold) of the initially plated cells was achieved with the combination of IL-1, IL-3, IL-4, IL-7, SLF, Flt3-L, and TNF- (Table 1, row 1). With this cytokine combination, approximately 90% of the cells showed typical DC morphology (Figure 1A-B and Figure 2). The removal of IL-7 from the cocktail caused a massive drop in cluster formation. The addition of myeloid-directed cytokines, such as GM-CSF and M-CSF, did not stimulate dendritic cluster formation from CLPs. Nor did DCs develop when IL-7 was added to GM-CSF and IL-4 (Table 1, row 12). No adherent macrophages developed in any cytokine combination, in accordance with our previous findings.22 Thus, the cytokine cocktail with the highest cluster formation capacity on day 4 (Table 1, row 1) was used for all in vitro experiments.                                View this table: [in this window] [in a new window]   Table 1. Effect of different cytokine combinations on cluster formation of common lymphoid progenitor-derived dendritic cells in culture View larger version (38K): [in this window] [in a new window]   Figure 1. Morphology of in vitro-generated DCs from CLPs and CMPs. (A) Typical clusters of DCs developing from 1 × 103 CLPs cultured with IL-1, IL-3, IL-4, IL-7, SLF, TNF-, and Flt3-L. Clusters were photographed directly in the Terasaki tray on an inverted microscope (objective × 40) on day 4 of culture. (B, C) Cells developing from 100 CLPs in the above cocktail on day 4 or from 5000 CMPs in IL-3, IL-4, SLF, TNF-, Flt-3L, and GM-CSF on day 6 were dissociated with EDTA, spun onto slides, and stained with Giemsa (objective × 60 oil). Almost all CLP-derived cells (B) and a substantial fraction of CMP-derived cells (C) displayed typical DC morphologies varying in size and nuclear shape. View larger version (60K): [in this window] [in a new window]   Figure 2. Phenotypic characterization of in vitro CLP- and CMP-derived DCs. Cells were cultured as described in "Material and methods." All cells were stained with anti-MHC class II and anti-CD11c (contour plot) plus 1 or 2 additional markers (histograms) by day 4 (CLP cultures) or day 6 (CMP cultures), respectively. Filled histograms show specific staining, and open histograms show isotype-matched controls of gated population in the contour plot (MHC class II+CD11c+). CLPs and CMPs do not express MHC class II (not shown). Although CLPs expressed no detectable MHC class II or CD11c (not shown), there was a gradual up-regulation of MHC class II and CD11c during the culture period. MHC class II+ CD11c+ cells were positive for DC-related antigens, including CD40, CD80, CD86 (Figure 2). CLP-derived DCs expressed low levels of DEC205 and were negative for other lineage markers, such as Mac-1, Gr-1, B220, and CD3 (Figure 2 and not shown). It has been reported that CD8 is expressed on DCs in vivo but not on DCs developed in vitro from TP.9 Consistent with these data, the DCs derived from cultured CLPs did not express CD8 (not shown). DCs in T-cell areas of lymph nodes express ELC28 and the MHC class II activator (CIITA) gene. RelB and PU.1 are reported to be critical genes in the development of CD8, but not CD8+, DCs.15,16 We therefore tested the expression of ELC, CIITA, RelB, and PU.1 in CLPs and CLP-derived DCs (MHC class II+ CD11c+) by RT-PCR 4 days after the initiation of cultures. CLP-derived DCs, but not freshly isolated CLPs, expressed ELC and CIITA, showing that DC commitment occured during culture. CLP-derived DCs expressed RelB and PU.1, as do all CD8+ and CD8 DC populations (Figure 3). Expression profiles of these genes did not fit with their proposed role in DC subset specification (lymphoid vs myeloid, CD8+ vs CD8) but were consistent with some role in the development or function of all types of DCs. View larger version (126K): [in this window] [in a new window]   Figure 3. Gene expression in CLPs and DCs. RT-PCR analysis of CLPs, CLP-derived DCs in culture, CD8+ and CD8 splenic DCs, total splenic cells, and CD8+ thymic DCs sorted from healthy animals. Although CLPs do not express CIITA, ELC, and RelB, CLP-derived DCs in culture, splenic and thymic DCs express these genes. No DC subsets expressed CD3. Uncultured splenic and thymic DCs expressed CD8+ mRNA. PCR conditions were as described in "Materials and methods." CLPs are more potent in generating DCs in vitro than early thymocyte progenitors on a single-cell basis To clarify the efficiency of DC development from CLPs, we determined the ability of single CLPs and TPs to differentiate to DCs. CLPs and TPs were cultured in numbers of 1, 2, and 5 cells per well. Results are shown in Table 2. On day 1, some CLPs and thymocyte progenitors began to increase in size and to show cytoplasmic extensions. Proliferative activity varied widely between wells. On day 4, cells in each well were counted, and DC read-out was evaluated by morphology in culture and by Giemsa staining of cytospin preparations. Eighty-three percent of single CLPs develop into cells with DC morphology. In contrast, 47% of single TPs developed into DCs. From single-sorted CLPs, the average number of DCs per well showing cells with DC morphology was 3.8. From the single-sorted TPs, the average number of DCs per well showing cells with DC morphology was 2.7. When we cultured 2 or 5 cells of each population, both DC plating efficiency and average number of DCs were always higher in CLPs than in TPs (Table 2).                                View this table: [in this window] [in a new window]   Table 2. Dendritic cell read-out from clone-sorted common lymphoid progenitors and early thymocyte progenitors CMPs and GMPs differentiate into DCs in vitro CMPs and GMPs were sorted and cultured at 2000 to 5000 cells per well in 96-well plates in 100 µL media containing various combinations of the cytokines IL-1, IL-3, IL-4, IL-7, SLF, Flt-3L, TNF-, and GM-CSF. DC read-out was evaluated by FACS analysis on days 4, 6, 8, and 10. Fresh media were added on days 4 and 8 in ongoing cultures. The most efficient DC read-out from CMPs and GMPs was achieved with a cytokine combination consisting of IL-3, IL-4, SLF, Flt-3L, TNF-, and GM-CSF on days 6 to 8 of culture (Figure 1C). With this combination, CMPs and GMPs expanded approximately 35 times and 20 times from the input cell numbers and gave rise to approximately 15% and 10% MHC class II+ CD11c+ DCs, respectively. GM-CSF or SLF deletion from the cultures caused the foremost drop in DC generation, proving those the most important of the evaluated cytokines for in vitro DC generation from myeloid-committed progenitors. Although CMP and GMP, like CLPs, express no detectable MHC class II or CD11c (not shown), those markers were up-regulated during the culture period. The MHC class II+CD11c+ cells expressed Mac-1 and DC-related antigens, including CD40, CD80, and CD86 (Figure 2). In vivo DC differentiation potential of CLPs, TPs, pro-T cells, CMPs, and GMPs We previously reported that CLPs have potent reconstitution activity for T and B cells; after intravenous injection into sublethally irradiated RAG-2-deficient mice, 1 × 103 CLPs give rise to approximately 1.5 × 107 B220+ splenic B cells and 1 × 107 CD3+ splenic T cells by 2 weeks and 5 weeks, respectively.22 To estimate the contribution of CLPs to the DC compartment in vivo, we transplanted graded numbers (1 × 103, 5 × 103, and 10 × 103) of CLPs to lethally irradiated host BM protected CD45 congenic recipient mice (see "Materials and methods"). Myelo-erythroid progeny were undetected as previously reported.22 Although reasonable DC progeny above background was not detectable with 1 × 103 transplanted CLPs, a significant fraction of cells with DC phenotype (MHC class II+CD11c+CD40+CD80+CD86+ CD8+/) was seen in spleen, thymus and lymph nodes 14 to 21 days after transplantation of 5 × 103 or more CLPs (Figure 4, Table 3). Most likely this reflected the fact that CLPs have a large burst size for B and T cells but, like TPs and pro-T cells, a small expansion potential for DC. Therefore, DC progeny became clearly evident only with high progenitor cell input. Sorted MHC class II+ CD11c+ cells displayed typical DC morphology after 12-hour incubation in complete media (not shown). At 2 weeks after transplantation, approximately 70% of CLP-derived and approximately 65% of host-derived splenic DCs showed CD8 expression. Four weeks after reconstitution, total numbers of CLP-derived DCs decreased significantly. On day 28, approximately 80% of CLP-derived splenic DCs were CD8+. In contrast, only approximately 35% of host-derived DCs were CD8+ at this time point (data not shown). View larger version (56K): [in this window] [in a new window]   Figure 4. CLPs give rise to DCs in vivo. CLPs were competitively transplanted into lethally irradiated CD45 congenic animals, together with host-type whole bone marrow (A). CD45 expression was used to gate on donor-type (CD45.1) and host-type (CD45.2) CD11c+-enriched, live splenocytes on day 15 after transplantation (B). Both CLP (upper panel) and host-derived (lower panel) cells were analyzed for DC phenotype by MHC class II+ and CD11c+ expression (C, contour plots). CLP-derived MHC class II+CD11c+ cells account for approximately 10% of donor-derived MHC class II+CD11c+ cells in a CD11c+-enriched sample. MHC class II+CD11c+ cells were further analyzed for CD8, CD40, CD80, and CD86 expression (C). Closed hisograms represent specific staining, and open histograms represent isotype-matched controls of the MHC class II+CD11c+ cells. On day 15, 69% of CLP-derived DCs and 63% of host-derived DCs were CD8+. Both CLP and host-derived DCs expressed low to intermediate levels of CD40, CD80, and CD86. Details are given in "Materials and methods."                                View this table: [in this window] [in a new window]   Table 3. Generation of dendritic cell progeny on day 15 in spleen and thymus from common lymphoid progenitors, common myeloid progenitors, early thymocyte progenitors, pro-T cells, and granulocyte-macrophage progenitors after transplantation into lethally irradiated animals We have shown that the earliest myeloid-committed progenitors, CMPs, can produce functional DCs of both CD8+ and CD8 phenotype after transplantation in vivo.24 Similarly, the downstream GMPs are capable of giving rise to both CD8+ and CD8 DCs in spleen and thymus, though with substantially lower efficiency than CMPs (Table 3 and not shown). To compare the contributions of lymphoid-committed and myeloid-committed progenitors to the entire DC compartment, we transplanted prospectively purified CLPs, TPs, pro-T cells, CMPs, and GMPs, along with host CD45 congenic bone marrow cells, into lethally irradiated hosts. Table 3 shows the mean number of donor-derived DC progeny (MHC class II+ CD11c+). On a per cell basis, transplanted CLPs are more efficient than the other progenitors in giving rise to thymic DCs. CLPs and CMPs are roughly equivalent, and both are far more efficient than TPs, pro-T cells, and GMPs in producing splenic DCs. CLPs represent 0.02%, CMPs 0.2%, and GMPs 0.4% of total nucleated cells in the bone marrow; approximately 2 × 104 CLPs, 20 × 104 CMPs, and 40 × 104 GMPs should reside in the femurs and tibias of both legs of a 6- to 8-week-old animal. Therefore, the transplanted 1 × 104 CLPs, 2 × 104 CMPs, and 4 × 104 GMPs represented approximately 50% the bone marrow equivalent of CLPs and approximately 10% the bone marrow equivalent of CMPs and GMPs in these bones, respectively. Similarly, approximately 3 × 104 CD25c-Kit+CD4loCD8 TP and 6 × 104 CD25+c-Kit+CD4CD8 pro-T cells exist in a 6- to 8-week-old thymus (each population accounted for 0.02% and 0.04% of all thymic cells, respectively, in our hands (data not shown). Hence, the transplanted 2 × 104 TPs and 3 × 104 pro-T cells represented 66% and 50% thymus equivalent, respectively. By transplanting CLPs and CMPs in increasing numbers, an approximate linear increase of progenitor-derived DCs was seen in spleen and thymus (data not shown). If their behavior on transplantation reflects the endogenous production of DCs by these progenitors, and if all DCs are produced through either CLPs or CMPs, we calculate that approximately 90% of splenic DCs and approximately 50% of thymic DCs are derived from CMPs and that approximately 10% splenic DCs and approximately 50% thymic DCs are of CLP origin (Table 3). CLP- and CMP-derived DCs are able to present allogeneic antigens efficiently We evaluated the antigen-presenting capacity of progenitor-derived DCs by a mixed lymphocyte reaction (MLR) assay. DCs developed in vitro from C57BL (H-2b) CLPs and from lineage-depleted bone marrow cells were irradiated on day 5 of culture and seeded in graded numbers. CLP-derived DCs were as efficient as bone marrow-derived DCs in their capacity to stimulate allogeneic (BALB/c: H-2d) lymph node cells (Figure 5A). CLP-derived MHC class II+CD11c+ DCs in thymus and spleen on day 15 after transplantation are as potent as CMP-derived and host-derived DCs to induce MLR (Figure 5B). View larger version (15K): [in this window] [in a new window]   Figure 5. DCs derived from CLPs and CMPs were functionally active in allogeneic mixed leukocyte reactions. (A) Stimulation of 105 allogeneic BALB/c lymph node cells by graded numbers (x-axis) of in vitro CLP-derived DCs (day 5 of culture) (closed diamonds) and by bone marrow (Lin)-derived DCs (day 5 of culture) (open squares). Cultures were grown and MLR was performed as described in "Materials and methods." Results are the means ± SE each with 3 to 6 wells per point. (B) MLR of in vivo CLP-, CMP-, and host-derived DCs sorted by high expression of CD11c and MHC class II. Sorted DCs were cultured in numbers as indicated for 12 hours in complete media without cytokines, and 2 × 105 nucleated BALB/c splenocytes were added. MLR was performed as described in "Materials and methods." (A, B) Results of 3 representative experiments are shown. Pro-B cells do not have detectable DC differentiation potential It was reported that CD19+ pro-B cells from BALB/c mice develop into DCs under the same culture conditions as TPs.25 We wanted to compare pro-B cells with CLPs and TPs in their ability to generate DCs. Rigorously purified pro-B cells (either IgM, NK1.1, B220+, CD43+, or IgM, CD19+, CD43+) were cultured at 103, 5 × 103, and 104 cells per well with IL-1, IL-3, IL-4, IL-7, SLF, Flt3-L, and TNF- or in the same cocktail without IL-4. We were unable to detect any DC progeny determined by surface phenotype and morphology on days 4 and 6 of cultures. We repeatedly transplanted 3 to 4 × 104 double-sorted pro-B cells (either IgM, NK1.1, B220+, CD43+, or IgM, CD19+, CD43+) and looked for DC read-out on days 8 and 15 after transplantation. Although pro-B cells generated a large amount of mature B cells, no DC progeny could be detected (not shown). MEP do not have significant DC differentiation potential MEPs cultured under the same conditions as CMPs and GMPs expanded approximately 5 times and only gave rise to 0.1% to 0.5% MHC class II+CD11c+ cells by day 6 of culture. However, when the MEP fraction was again divided by CD34 expression, the less-positive fraction did not give rise to DCs. It seems likely, then, that a few progenitors at the phenotype margin between CMP and MEP have some in vitro DC potential. This could be due either to a small number of CMP contaminants among the 2000 to 5000 MEPs cultured or to a few MEPs at the phenotypic margin that may be able to differentiate into DCs but not to granulocytes or macrophages. By transplanting 3 × 104 MEPs (accounting for 33% of bone marrow equivalent of those progenitors), no DC read-out could be detected on days 8 and 15 after transplantation (not shown). Therefore, MEPs have no significant, if any, DC differentiation potential.     Discussion Top Abstract Introduction Materials and methods Results Discussion References We have previously shown that CMPs efficiently give rise to both CD8+ and CD8 DC subsets.24 Here we show that the downstream granulocyte-macrophage-restricted progenitors, but not the megakaryocyte-erythrocyte-restricted progenitors, give rise to DCs, and we compare the DC potentials of the myeloid-committed progenitors to lymphoid-committed progenitors. We show directly that CLPs, the earliest lymphoid-restricted progenitors, are capable of differentiating into both CD8+ and CD8 functional DCs. This differentiation activity into DCs is preserved in early T-cell progenitors, declining along with T-cell maturation, but is absent in B-cell progenitors. Thus, in addition to the DC developmental pathway from CMP, there is a DC developmental pathway initiated at the CLP, which continues to T-cell-committed progenitors (Figure 6). View larger version (48K): [in this window] [in a new window]   Figure 6. Proposed differentiation pathways from HSC to DC. The earliest CLPs and CMPs in bone marrow are capable of developing into DCs of both CD8+ and CD8 phenotypes. DC development potential is preserved in early T-cell progenitors and declines along with T-cell maturation as well as during granulocyte-macrophage commitment but is absent in B-cell progenitors and megakaryocyte-erythrocyte progenitors. It has been shown that the early thymocyte progenitor (TP) and pro-T cell populations contain cells that are capable of differentiating into CD8+ DCs in the thymus and secondary lymphoid organs7,20 and that give rise to DCs in vitro.9 Our data indicate that approximately 80% of single CLP and approximately 50% of single TPs can differentiate into DCs. Thus, the developmental potential of DCs is efficiently maintained during the transition from CLP to TP stages. It has been reported that pro-B cells in BALB/c mice can differentiate into DCs in vitro, though at a low frequency.25 In addition, pro-B cells from Pax5/ mice were able to give rise to DCs in vitro.32 We did not detect DC development from purified pro-B cells from C57BL mice in vivo or in vitro, with doses as high as 104 cells. Because pro-B cells in Pax5/ mice are capable of differentiating into myelomonocytic cells, DC differentiation from Pax5/ pro-B cells might not reflect physiological differentiation potentials. Elsewhere we have shown that CLPs and pro-T cells, but not pro-B cells, can be redirected from lymphoid to myelomonocytic development through the introduction of transgenes encoding hIL-2R or hGM-CSFR into these cells and culturing the transfectants with the cognate human cytokine.33 It is interesting that the natural loss of DC generative capacity and the revealed loss of myeloid conversion from the lymphoid pathway occur at similar differentiation checkpoints. An important question in DC biology has been whether CD8 expression on DCs marks lymphoid origin. Our data indicate that CLPs, as well as CMPs and GMPs, give rise to both CD8+ and CD8 DCs in spleen and that virtually all thymic DCs derived from either CLPs or CMPs and GMPs were CD8+.24 Although 1 in 2780 cells with the CMP phenotype is capable of differentiating into B cells on OP9 stromal layers,23 it seems unlikely that approximately 10 CMPs with B-cell differentiation capacity within the transplanted 2 × 104 CMPs account for most CMP-derived DCs (80%-90%) that express CD8+.24 In addition, GMPs generate CD8+ and CD8 DCs but not B cells, and we here show that pro-B cells do not generate DCs as discussed above. These data indicate that CD8 expression does not delineate the ontogeny of DC; rather, both types of DC can develop from either myeloid-restricted or lymphoid-restricted stages of hematopoietic differentiation. In a recent report, it was shown that TPs are capable of giving rise to splenic CD8 DCs.34 According to the authors, these CD8 DCs were possibly missed before because of the DC enrichment technique. In addition, it has been reported that TPs develop into CD8/low DCs in lymph nodes.35 We have not tested whether CD8 expression represents a stage of DC maturation or whether CD8+ and CD8 DCs represent 2 distinct and independent DC types. In our study, there was a gradual increase in the percentage of CLP-derived CD8+ DC during the 2 to 4 weeks after transplantation. A similar observation was made earlier for TP-derived DCs.8,36 Therefore, CD8 expression on DCs might be maturation-stage dependent. In support of this hypothesis, it has been reported that CD8 is an activation marker of Langerhans cells after antigen uptake and migration into draining lymph nodes.37,38 Additionally, it has been shown that CD8+ DCs reside in the T-cell areas of secondary lymphoid organs, whereas CD8 DCs are found in the marginal zones39,40 and marginal zone DCs have been proposed to be the immature precursors of DC in the T-cell areas.41-43 On the other hand, if CD8+ and CD8 DCs develop independently, it is also possible that increased CD8+ DC detection after the transplantation of committed progenitors might result from a longer half-life of CD8+ DCs. Data are conflicting on the half-lives of these DC subsets.39,44 It is of interest to know whether DCs derived from CLPs or CMPs have diverse, specific functions. Because each progenitor can give rise to CD8+ and CD8 DCs, previous experiments using CD8 expression on DCs to define a "lymphoid" origin are not helpful on this point.45-52 Our data show that CLP-derived DCs are as potent as CMP-derived DCs, at least for T-cell stimulation by presenting allogeneic antigens (Figure 5). However, to test for differences between CLP- and CMP-derived DCs, more detailed functional analyses are required. It is also important to know whether CMP- and CLP-derived DC subsets use the differentiation machinery common to myeloid and lymphoid differentiation or whether each subset requires molecular events specific for either myeloid or lymphoid lineage. Our data show that CLPs express the IL-7R and require IL-7 to differentiate into DCs. On the other hand, myeloid-related cytokines, such as GM-CSF and M-CSF, have no effect on DC development from CLP, though GM-CSF is important for DC development from myeloid progenitors, as shown here and previously.11,14,53,54 Because IL-7 is an indispensable cytokine for both T- and B-cell development,55,56 but not for myeloid development, the differentiation machinery of DCs from these lymphoid progenitors may be related to molecular events downstream of the IL-7R. Mice deficient in the transcription factors RelB,15 PU.1,16 and Ikaros17 reportedly lack CD8 DC but not CD8+ DC. However, because CD8 is not a marker of lymphoid derivation,24 these data no longer suggest that these transcription factors are deterministic for myeloid or lymphoid DC differentiation pathways. Furthermore, we show that both RelB and PU.1 are expressed in purified CD8+ and CD8 splenic DCs and in CLP-derived DCs and that PU.1 has been already turned on at both CLP and CMP (Figure 3).23 Although these nonquantitative PCR results do not reflect the amount of transcribed mRNA, these factors may play an important role in the development of myeloid and lymphoid DC, irrespective of their CD8 expression. Indeed, another mouse strain deficient in PU.1 reportedly lacks both CD8+ and CD8 DC.57 Further studies are required to understand the role of these transcription factors in each pathway. Parallel reconstitution experiments using purified CMPs and CLPs show that these populations are roughly equivalent at producing splenic DCs. Because CMPs are more frequent than CLPs, it is reasonable to propose that the contribution of CMPs to total splenic DCs is approximately 10-fold higher than CLPs; CMPs and CLPs likely contribute equally to the formation of the thymic DC compartment. Furthermore, there were no apparent differences in absolute or relative numbers of CD8+ and CD8 DC in the spleens of IL-7-deficient and wild-type mice (M.G.M. et al, unpublished data, November 2000). Because IL-7 is necessary for CLPs to differentiate into DCs, at least in vitro, these data support our findings that the contribution of CLPs to the splenic DC compartment is smaller than that of CMPs. In conclusion, lymphoid-restricted progenitors can generate DCs, though CD8 expression is not a marker for "lymphoid" DCs.24 The ability to obtain DCs from purified lymphoid-restricted CLPs and myeloid-restricted CMPs should provide the means to clarify the differences in the developmental mechanisms and functions between these DC subsets of different lineal origins.     Acknowledgments We thank S.-I. Nishikawa for the anti-IL-7R antibody, L. Jerabek for excellent laboratory management, V. Braunstein for antibody preparation, the Stanford FACS facility for flow cytometer maintenance, and L. Hidalgo, B. Lavarro, and D. Escoto for animal care.     Footnotes Submitted November 28, 2000; accepted February 5, 2001. Supported in part by a fellowship from Deutsche Krebshilfe, Dr Mildred-Scheel-Stiftung für Krebsforschung (M.G.M.), National Institutes of Health training grant 5T32 AI-07290 (D.T.), a Jose Carreras International Leukemia Society grant (K.A.), the Claudia Adams Barr Program (K.A.), and a United States Public Health Service grant (CA42551) (I.L.W.). 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: Markus G. Manz, Department of Pathology and Developmental Biology, B261 Beckman Center, Stanford University School of Medicine, 279 Campus Dr, Stanford CA 94305-5428; e-mail: manz{at}leland.stanford.edu.     References Top Abstract Introduction Materials and methods Results Discussion References 1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245-252[CrossRef][Medline] [Order article via Infotrieve]. 2. Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811[CrossRef][Medline] [Order article via Infotrieve]. 3. Shortman K, Caux C. Dendritic cell development: multiple pathways to nature's adjuvants. Stem Cells. 1997;15:409-419[Abstract/Free Full Text]. 4. Steinman RM, Pack M, Inaba K. Dendritic cells in the T-cell areas of lymphoid organs. Immunol Rev. 1997;156:25-37[CrossRef][Medline] [Order article via Infotrieve]. 5. Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells [In Process Citation]. J Exp Med. 2000;191:411-416[Free Full Text]. 6. Vremec D, Zorbas M, Scollay R, et al. The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J Exp Med. 1992;176:47-58[Abstract/Free Full Text]. 7. 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. 1993;362:761-763[CrossRef][Medline] [Order article via Infotrieve]. 8. Wu L, Li CL, Shortman K. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J Exp Med. 1996;184:903-911[Abstract/Free Full Text]. 9. Saunders D, Lucas K, Ismaili J, et al. Dendritic cell development in culture from thymic precursor cells in the absence of granulocyte/macrophage colony-stimulating factor. J Exp Med. 1996;184:2185-2196[Abstract/Free Full Text]. 10. 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 Methods. 1992;154:253-264[CrossRef][Medline] [Order article via Infotrieve]. 11. Inaba K, Inaba M, Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992;176:1693-1702[Abstract/Free Full Text]. 12. Inaba K, Inaba M, Deguchi M, et al. Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow. Proc Natl Acad Sci U S A. 1993;90:3038-3042[Abstract/Free Full Text]. 13. Schreurs MW, Eggert AA, de Boer AJ, Figdor CG, Adema GJ. Generation and functional characterization of mouse monocyte-derived dendritic cells. Eur J Immunol. 1999;29:2835-2841[CrossRef][Medline] [Order article via Infotrieve]. 14. 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 down-regulated by tumor necrosis factor alpha. J Exp Med. 1994;179:1109-1118[Abstract/Free Full Text]. 15. Wu L, D'Amico A, Winkel KD, Suter M, Lo D, Shortman K. RelB is essential for the development of myeloid-related CD8-dendritic cells but not of lymphoid-related CD8+ dendritic cells. Immunity. 1998;9:839-847[CrossRef][Medline] [Order article via Infotrieve]. 16. Guerriero A, Langmuir PB, Spain LM, Scott EW. PU.1 is required for myeloid-derived but not lymphoid-de rived dendritic cells. Blood. 2000;95:879-885[Abstract/Free Full Text]. 17. Wu L, Nichogiannopoulou A, Shortman K, Georgopoulos K. Cell-autonomous defects in dendritic cell populations of Ikaros mutant mice point to a developmental relationship with the lymphoid lineage. Immunity. 1997;7:483-492[CrossRef][Medline] [Order article via Infotrieve]. 18. Rodewald HR, Brocker T, Haller C. Developmental dissociation of thymic dendritic cell and thymocyte lineages revealed in growth factor receptor mutant mice. Proc Natl Acad Sci U S A. 1999;96:15068-15073[Abstract/Free Full Text]. 19. Radtke F, Ferrero I, Wilson A, Lees R, Aguet M, MacDonald HR. Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells. J Exp Med. 2000;191:1085-1094[Abstract/Free Full Text]. 20. Wu L, Antica M, Johnson GR, Scollay R, Shortman K. Developmental potential of the earliest precursor cells from the adult mouse thymus. J Exp Med. 1991;174:1617-1627[Abstract/Free Full Text]. 21. Weissman IL. Stem cells, clonal progenitors, and commitment to the three lymphocyte lineages: T, B, and NK cells [comment]. Immunity. 1994;1:529-531[CrossRef][Medline] [Order article via Infotrieve]. 22. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91:661-672[CrossRef][Medline] [Order article via Infotrieve]. 23. Akashi K, Traver D, Miyamoto T, Weissman IL. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature. 2000;404:193-197[CrossRef][Medline] [Order article via Infotrieve]. 24. Traver D, Akashi K, Manz M, et al. Development of CD8+ dendritic cells from a common myeloid progenitor. Science. 2000;290:2152-2154[Abstract/Free Full Text]. 25. Bjorck P, Kincade PW. CD19+ pro-B cells can give rise to dendritic cells in vitro. J Immunol. 1998;161:5795-5799[Abstract/Free Full Text]. 26. Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci U S A. 2000;97:7521-7526[Abstract/Free Full Text]. 27. Zhang Y, Zhang YY, Ogata M, et al. Transforming growth factor-1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway. Blood. 1999;93:1208-1220[Abstract/Free Full Text]. 28. Ngo VN, Tang HL, Cyster JG. Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J Exp Med. 1998;188:181-191[Abstract/Free Full Text]. 29. Ryseck RP, Bull P, Takamiya M, et al. RelB, a new Rel family transcription activator that can interact with p50-NF-kappa B. Mol Cell Biol. 1992;12:674-684[Abstract/Free Full Text]. 30. Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene [see comments]. Cell. 1990;61:113-124[CrossRef][Medline] [Order article via Infotrieve]. 31. Vremec D, Pooley J, Hochrein H, Wu L, Shortman K. CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen. J Immunol. 2000;164:2978-2986[Abstract/Free Full Text]. 32. Nutt SL, Heavey B, Rolink AG, Busslinger M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5 [see comments]. Nature. 1999;401:556-562[CrossRef][Medline] [Order article via Infotrieve]. 33. Kondo M, Scherer DC, Miyamoto T, et al. Cell fate conversion of lymphoid committed progenitors by instructive actions of cytokines. Nature. 2000;407:383-386[CrossRef][Medline] [Order article via Infotrieve]. 34. Martin P, del Hoyo GM, Anjuere F, et al. Concept of lymphoid versus myeloid dendritic cell lineages revisited: both CD8 and CD8+ dendritic cells are generated from CD4low lymphoid-committed precursors. Blood. 2000;96:2511-2519[Abstract/Free Full Text]. 35. Kronin V, Wu L, Gong S, Nussenzweig MC, Shortman K. DEC-205 as a marker of dendritic cells with regulatory effects on CD8 T cell responses. Int Immunol. 2000;12:731-735[Abstract/Free Full Text]. 36. Wu L, Vremec D, Ardavin C, et al. Mouse thymus dendritic cells: kinetics of development and changes in surface markers during maturation. Eur J Immunol. 1995;25:418-425[Medline] [Order article via Infotrieve]. 37. Anjuere F, Martin P, Ferrero I, et al. Definition of dendritic cell subpopulations present in the spleen, Peyer's patches, lymph nodes, and skin of the mouse. Blood. 1999;93:590-598[Abstract/Free Full Text]. 38. Merad M, Fong L, Bogenberger J, Engleman EG. Differentiation of myeloid dendritic cells into CD8+ dendritic cells in vivo. Blood. 2000;96:1865-1872[Abstract/Free Full Text]. 39. Leenen PJ, Radosevic K, Voerman JS, et al. Heterogeneity of mouse spleen dendritic cells: in vivo phagocytic activity, expression of macrophage markers, and subpopulation turnover. J Immunol. 1998;160:2166-2173[Abstract/Free Full Text]. 40. Pulendran B, Lingappa J, Kennedy MK, et al. Developmental pathways of dendritic cells in vivo: distinct function, phenotype, and localization of dendritic cell subsets in FLT3 ligand-treated mice. J Immunol. 1997;159:2222-2231[Abstract/Free Full Text]. 41. Agger R, Witmer-Pack M, Romani N, et al. 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 Leukoc Biol. 1992;52:34-42[Abstract]. 42. Sato N, Ahuja SK, Quinones M, et al. CC chemokine receptor (CCR)2 is required for langerhans cell migration and localization of T helper cell type 1 (Th1)-inducing dendritic cells: absence of CCR2 shifts the Leishmania major-resistant phenotype to a susceptible state dominated by Th2 cytokines, B cell outgrowth, and sustained neutrophilic inflammation. J Exp Med. 2000;192:205-218[Abstract/Free Full Text]. 43. De Smedt T, Pajak B, Muraille E, et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med. 1996;184:1413-1424[Abstract/Free Full Text]. 44. Kamath A, Tough D, Shortman K. Lifespan of different dendritic cell populations in lymphoid organs. Paper presented at: the Sixth International Symposium on Dendritic Cells; May 26, 2000; Port Douglas, Queensland, Australia. 45. Maldonado-Lopez R, De Smedt T, Michel P, et al. CD8+ and CD8 subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med. 1999;189:587-592[Abstract/Free Full Text]. 46. Maldonado-Lopez R, De Smedt T, Pajak B, et al. Role of CD8+ and CD8 dendritic cells in the induction of primary immune responses in vivo. J Leukoc Biol. 1999;66:242-246[Abstract]. 47. Ohteki T, Fukao T, Suzue K, et al. Interleukin 12-dependent interferon gamma production by CD8+ lymphoid dendritic cells. J Exp Med. 1999;189:1981-1986[Abstract/Free Full Text]. 48. Pulendran B, Smith JL, Caspary G, et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci U S A. 1999;96:1036-1041[Abstract/Free Full Text]. 49. Suss G, Shortman K. A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis. J Exp Med. 1996;183:1789-1796[Abstract/Free Full Text]. 50. Kronin V, Winkel K, Suss G, et al. A subclass of dendritic cells regulates the response of naive CD8 T cells by limiting their IL-2 production. J Immunol. 1996;157:3819-3827[Abstract]. 51. Aliberti J, Reis E, Sousa C, Schito M, et al. CCR5 provides a signal for microbial induced production of IL-12 by CD8+ dendritic cells. Nat Immunol. 2000;1:83-87[CrossRef][Medline] [Order article via Infotrieve]. 52. Winkel KD, Kronin V, Krummel MF, Shortman K. The nature of the signals regulating CD8 T cell proliferative responses to CD8+ or CD8 dendritic cells. Eur J Immunol. 1997;27:3350-3359[Medline] [Order article via Infotrieve]. 53. Santiago-Schwarz F, Divaris N, Kay C, Carsons SE. Mechanisms of tumor necrosis factor granulocyte macrophage-colony-stimulating factor-induced dendritic cell development. Blood. 1993;82:3019-3028[Abstract/Free Full Text]. 54. Reid CD, 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. 1992;149:2681-2688[Abstract]. 55. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell. 1997;89:1033-1041[CrossRef][Medline] [Order article via Infotrieve]. 56. Kondo M, Akashi K, Domen J, Sugamura K, Weissman IL. Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common gamma chain-deficient mice. Immunity. 1997;7:155-162[CrossRef][Medline] [Order article via Infotrieve]. 57. Anderson KL, Perkin H, Surh CD, Venturini S, Maki RA, Torbett BE. Transcription factor PU.1 is necessary for development of thymic and myeloid progenitor-derived dendritic cells. J Immunol. 2000;164:1855-1861[Abstract/Free Full Text]. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. K. Vogt, A. Link, J. Perrin, D. Finke, and S. A. Luther Novel function for interleukin-7 in dendritic cell development Blood, April 23, 2009; 113(17): 3961 - 3968. [Abstract] [Full Text] [PDF] M. Merad and M. G. Manz Dendritic cell homeostasis Blood, April 9, 2009; 113(15): 3418 - 3427. [Abstract] [Full Text] [PDF] T. Serwold, L. I. Richie Ehrlich, and I. L. Weissman Reductive isolation from bone marrow and blood implicates common lymphoid progenitors as the major source of thymopoiesis Blood, January 22, 2009; 113(4): 807 - 815. [Abstract] [Full Text] [PDF] I. L. 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The Inhibitory HVEM-BTLA Pathway Counter Regulates Lymphotoxin Receptor Signaling to Achieve Homeostasis of Dendritic Cells J. Immunol., January 1, 2008; 180(1): 238 - 248. [Abstract] [Full Text] [PDF] F. Ishikawa, H. Niiro, T. Iino, S. Yoshida, N. Saito, S. Onohara, T. Miyamoto, H. Minagawa, S.-i. Fujii, L. D. Shultz, et al. The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways Blood, November 15, 2007; 110(10): 3591 - 3660. [Abstract] [Full Text] [PDF] M. Kawazu, G. Yamamoto, M. Yoshimi, K. Yamamoto, T. Asai, M. Ichikawa, S. Seo, M. Nakagawa, S. Chiba, M. Kurokawa, et al. Expression Profiling of Immature Thymocytes Revealed a Novel Homeobox Gene That Regulates Double-Negative Thymocyte Development J. Immunol., October 15, 2007; 179(8): 5335 - 5345. [Abstract] [Full Text] [PDF] L. Gutierrez, T. Nikolic, T. B. van Dijk, H. Hammad, N. Vos, M. Willart, F. Grosveld, S. Philipsen, and B. N. Lambrecht Gata1 regulates dendritic-cell development and survival Blood, September 15, 2007; 110(6): 1933 - 1941. [Abstract] [Full Text] [PDF] R. S. Welner, R. Pelayo, K. P. Garrett, X. Chen, S. S. Perry, X.-H. Sun, B. L. Kee, and P. W. Kincade Interferon-producing killer dendritic cells (IKDCs) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors Blood, June 1, 2007; 109(11): 4825 - 4931. [Abstract] [Full Text] [PDF] M. Sanyal, J. W. Tung, H. Karsunky, H. Zeng, L. Selleri, I. L. Weissman, L. A. Herzenberg, and M. L. Cleary B-cell development fails in the absence of the Pbx1 proto-oncogene Blood, May 15, 2007; 109(10): 4191 - 4199. [Abstract] [Full Text] [PDF] B. C. Harman, J. P. Miller, N. Nikbakht, R. Gerstein, and D. Allman Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors Blood, August 1, 2006; 108(3): 878 - 885. [Abstract] [Full Text] [PDF] J. Diao, E. Winter, C. Cantin, W. Chen, L. Xu, D. Kelvin, J. Phillips, and M. S. Cattral In Situ Replication of Immediate Dendritic Cell (DC) Precursors Contributes to Conventional DC Homeostasis in Lymphoid Tissue. J. Immunol., June 15, 2006; 176(12): 7196 - 7206. [Abstract] [Full Text] [PDF] I. Mende, H. Karsunky, I. L. Weissman, E. G. Engleman, and M. Merad Flk2+ myeloid progenitors are the main source of Langerhans cells Blood, February 15, 2006; 107(4): 1383 - 1390. [Abstract] [Full Text] [PDF] N. Onai, A. Obata-Onai, R. Tussiwand, A. Lanzavecchia, and M. G. Manz Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon-producing and dendritic cell development J. Exp. Med., January 23, 2006; 203(1): 227 - 238. [Abstract] [Full Text] [PDF] D. K. Fogg, C. Sibon, C. Miled, S. Jung, P. Aucouturier, D. R. Littman, A. Cumano, and F. Geissmann A Clonogenic Bone Marrow Progenitor Specific for Macrophages and Dendritic Cells Science, January 6, 2006; 311(5757): 83 - 87. [Abstract] [Full Text] [PDF] S. Takeuchi and S. I. Katz Use of interleukin 7 receptor-{alpha} knockout donor cells demonstrates the lymphoid independence of dendritic cells Blood, January 1, 2006; 107(1): 184 - 186. [Abstract] [Full Text] [PDF] G.-X. Yang, Z.-X. Lian, K. Kikuchi, Y. Moritoki, A. A. Ansari, Y.-J. Liu, S. Ikehara, and M. E. Gershwin Plasmacytoid Dendritic Cells of Different Origins Have Distinct Characteristics and Function: Studies of Lymphoid Progenitors versus Myeloid Progenitors J. Immunol., December 1, 2005; 175(11): 7281 - 7287. [Abstract] [Full Text] [PDF] A. Mao, V. Paharkova-Vatchkova, J. Hardy, M. M. Miller, and S. Kovats Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells J. Immunol., October 15, 2005; 175(8): 5146 - 5151. [Abstract] [Full Text] [PDF] R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity J. Immunol., September 15, 2005; 175(6): 3674 - 3680. [Abstract] [Full Text] [PDF] K. P. A. MacDonald, V. Rowe, H. M. Bofinger, R. Thomas, T. Sasmono, D. A. Hume, and G. R. Hill The Colony-Stimulating Factor 1 Receptor Is Expressed on Dendritic Cells during Differentiation and Regulates Their Expansion J. Immunol., August 1, 2005; 175(3): 1399 - 1405. [Abstract] [Full Text] [PDF] T. Hieronymus, T. C. Gust, R. D. Kirsch, T. Jorgas, G. Blendinger, M. Goncharenko, K. Supplitt, S. Rose-John, A. M. Muller, and M. Zenke Progressive and Controlled Development of Mouse Dendritic Cells from Flt3+CD11b+ Progenitors In Vitro J. Immunol., March 1, 2005; 174(5): 2552 - 2562. [Abstract] [Full Text] [PDF] T. Tamura, P. Tailor, K. Yamaoka, H. J. Kong, H. Tsujimura, J. J. O'Shea, H. Singh, and K. Ozato IFN Regulatory Factor-4 and -8 Govern Dendritic Cell Subset Development and Their Functional Diversity J. Immunol., March 1, 2005; 174(5): 2573 - 2581. [Abstract] [Full Text] [PDF] M.-L. Arcangeli, C. Lancrin, F. Lambolez, C. Cordier, E. Schneider, B. Rocha, and S. Ezine Extrathymic Hemopoietic Progenitors Committed to T Cell Differentiation in the Adult Mouse J. Immunol., February 15, 2005; 174(4): 1980 - 1988. [Abstract] [Full Text] [PDF] R. J. Steptoe, J. M. Ritchie, L. K. Jones, and L. C. Harrison Autoimmune Diabetes Is Suppressed by Transfer of Proinsulin-Encoding Gr-1+ Myeloid Progenitor Cells That Differentiate In Vivo Into Resting Dendritic Cells Diabetes, February 1, 2005; 54(2): 434 - 442. [Abstract] [Full Text] [PDF] T. E. Toliver-Kinsky, W. Cui, E. D. Murphey, C. Lin, and E. R. Sherwood Enhancement of Dendritic Cell Production by Fms-Like Tyrosine Kinase-3 Ligand Increases the Resistance of Mice to a Burn Wound Infection J. Immunol., January 1, 2005; 174(1): 404 - 410. [Abstract] [Full Text] [PDF] L. Chicha, D. Jarrossay, and M. G. Manz Clonal Type I Interferon-producing and Dendritic Cell Precursors Are Contained in Both Human Lymphoid and Myeloid Progenitor Populations J. Exp. Med., December 6, 2004; 200(11): 1519 - 1524. [Abstract] [Full Text] [PDF] J. Lee, S. N. Sait, and M. Wetzler Characterization of dendritic-like cells derived from t(9;22) acute lymphoblastic leukemia blasts Int. Immunol., October 1, 2004; 16(10): 1377 - 1389. [Abstract] [Full Text] [PDF] J. Diao, E. Winter, W. Chen, C. Cantin, and M. S. Cattral Characterization of Distinct Conventional and Plasmacytoid Dendritic Cell-Committed Precursors in Murine Bone Marrow J. Immunol., August 1, 2004; 173(3): 1826 - 1833. [Abstract] [Full Text] [PDF] S. Tabrizifard, A. Olaru, J. Plotkin, M. Fallahi-Sichani, F. Livak, and H. T. Petrie Analysis of Transcription Factor Expression during Discrete Stages of Postnatal Thymocyte Differentiation J. Immunol., July 15, 2004; 173(2): 1094 - 1102. [Abstract] [Full Text] [PDF] H. C. O'Neill, H. L. Wilson, B. Quah, J. L. Abbey, G. Despars, and K. Ni Dendritic Cell Development in Long-Term Spleen Stromal Cultures Stem Cells, July 1, 2004; 22(4): 475 - 486. [Abstract] [Full Text] [PDF] M. Mohty, E. Jourdan, N. B. Mami, N. Vey, G. Damaj, D. Blaise, D. Isnardon, D. Olive, and B. Gaugler Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia Blood, June 15, 2004; 103(12): 4666 - 4668. [Abstract] [Full Text] [PDF] X. Peng, S. F. Hussain, and Y. Paterson The Ability of Two Listeria monocytogenes Vaccines Targeting Human Papillomavirus-16 E7 to Induce an Antitumor Response Correlates with Myeloid Dendritic Cell Function J. Immunol., May 15, 2004; 172(10): 6030 - 6038. [Abstract] [Full Text] [PDF] M. Franchini, H. Hefti, S. Vollstedt, B. Glanzmann, M. Riesen, M. Ackermann, P. Chaplin, K. Shortman, and M. Suter Dendritic Cells from Mice Neonatally Vaccinated with Modified Vaccinia Virus Ankara Transfer Resistance against Herpes Simplex Virus Type I to Naive One-Week-Old Mice J. Immunol., May 15, 2004; 172(10): 6304 - 6312. [Abstract] [Full Text] [PDF] H. C. O'Neill and H. L. Wilson Limitations with in vitro production of dendritic cells using cytokines J. Leukoc. Biol., April 1, 2004; 75(4): 600 - 603. [Abstract] [Full Text] [PDF] L. Borghesi, L.-Y. Hsu, J. P. Miller, M. Anderson, L. Herzenberg, L. Herzenberg, M. S. Schlissel, D. Allman, and R. M. Gerstein B Lineage-specific Regulation of V(D)J Recombinase Activity Is Established in Common Lymphoid Progenitors J. Exp. Med., February 17, 2004; 199(4): 491 - 502. [Abstract] [Full Text] [PDF] 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] J. T. Pribila, A. A. Itano, K. L. Mueller, and Y. Shimizu The {alpha}1{beta}1 and {alpha}E{beta}7 Integrins Define a Subset of Dendritic Cells in Peripheral Lymph Nodes with Unique Adhesive and Antigen Uptake Properties J. Immunol., January 1, 2004; 172(1): 282 - 291. [Abstract] [Full Text] [PDF] A J Stagg, A L Hart, S C Knight, and M A Kamm The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria Gut, October 1, 2003; 52(10): 1522 - 1529. [Abstract] [Full Text] [PDF] H. E. Porritt, K. Gordon, and H. T. Petrie Kinetics of Steady-state Differentiation and Mapping of Intrathymic-signaling Environments by Stem Cell Transplantation in Nonirradiated Mice J. Exp. Med., September 15, 2003; 198(6): 957 - 962. [Abstract] [Full Text] [PDF] H. L. Wilson and H. C. O'Neill Identification of differentially expressed genes representing dendritic cell precursors and their progeny Blood, September 1, 2003; 102(5): 1661 - 1669. [Abstract] [Full Text] [PDF] A. D'Amico and L. Wu The Early Progenitors of Mouse Dendritic Cells and Plasmacytoid Predendritic Cells Are within the Bone Marrow Hemopoietic Precursors Expressing Flt3 J. Exp. Med., July 21, 2003; 198(2): 293 - 303. [Abstract] [Full Text] [PDF] H. Karsunky, M. Merad, A. Cozzio, I. L. Weissman, and M. G. Manz Flt3 Ligand Regulates Dendritic Cell Development from Flt3+ Lymphoid and Myeloid-committed Progenitors to Flt3+ Dendritic Cells In Vivo J. Exp. Med., July 21, 2003; 198(2): 305 - 313. [Abstract] [Full Text] [PDF] C.-M. Sun, L. Fiette, M. Tanguy, C. Leclerc, and R. Lo-Man Ontogeny and innate properties of neonatal dendritic cells Blood, July 15, 2003; 102(2): 585 - 591. [Abstract] [Full Text] [PDF] S. Naik, D. Vremec, L. Wu, M. O'Keeffe, and K. Shortman CD8{alpha}+ mouse spleen dendritic cells do not originate from the CD8{alpha}- dendritic cell subset Blood, July 15, 2003; 102(2): 601 - 604. [Abstract] [Full Text] [PDF] J. Iwasaki-Arai, H. Iwasaki, T. Miyamoto, S. Watanabe, and K. Akashi Enforced Granulocyte/Macrophage Colony-stimulating Factor Signals Do Not Support Lymphopoiesis, but Instruct Lymphoid to Myelomonocytic Lineage Conversion J. Exp. Med., May 19, 2003; 197(10): 1311 - 1322. [Abstract] [Full Text] [PDF] L. Corcoran, I. Ferrero, D. Vremec, K. Lucas, J. Waithman, M. O'Keeffe, L. Wu, A. Wilson, and K. Shortman The Lymphoid Past of Mouse Plasmacytoid Cells and Thymic Dendritic Cells J. Immunol., May 15, 2003; 170(10): 4926 - 4932. [Abstract] [Full Text] [PDF] P. Szabolcs, K.-D. Park, M. Reese, L. Marti, G. Broadwater, and J. Kurtzberg Absolute Values of Dendritic Cell Subsets in Bone Marrow, Cord Blood, and Peripheral Blood Enumerated by a Novel Method Stem Cells, May 1, 2003; 21(3): 296 - 303. [Abstract] [Full Text] [PDF] T. Nikolic, M. F. T. R. d. Bruijn, M. B. Lutz, and P. J. M. Leenen Developmental stages of myeloid dendritic cells in mouse bone marrow Int. Immunol., April 1, 2003; 15(4): 515 - 524. [Abstract] [Full Text] [PDF] E. Donskoy and I. Goldschneider Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions J. Immunol., April 1, 2003; 170(7): 3514 - 3521. [Abstract] [Full Text] [PDF] H. Tsujimura, T. Tamura, C. Gongora, J. Aliberti, C. Reis e Sousa, A. Sher, and K. Ozato ICSBP/IRF-8 retrovirus transduction rescues dendritic cell development in vitro Blood, February 1, 2003; 101(3): 961 - 969. [Abstract] [Full Text] [PDF] B. J. Weigel, N. Nath, P. A. Taylor, A. Panoskaltsis-Mortari, W. Chen, A. M. Krieg, K. Brasel, and B. R. Blazar Comparative analysis of murine marrow-derived dendritic cells generated by Flt3L or GM-CSF/IL-4 and matured with immune stimulatory agents on the in vivo induction of antileukemia responses Blood, December 1, 2002; 100(12): 4169 - 4176. [Abstract] [Full Text] [PDF] L. S. van Rijt, J.-B. Prins, P. J. M. Leenen, K. Thielemans, V. C. de Vries, H. C. Hoogsteden, and B. N. Lambrecht Allergen-induced accumulation of airway dendritic cells is supported by an increase in CD31hiLy-6Cneg bone marrow precursors in a mouse model of asthma Blood, November 15, 2002; 100(10): 3663 - 3671. [Abstract] [Full Text] [PDF] T. Kouro, V. Kumar, and P. W. Kincade Relationships between early B- and NK-lineage lymphocyte precursors in bone marrow Blood, November 15, 2002; 100(10): 3672 - 3680. [Abstract] [Full Text] [PDF] M. Lu, H. Kawamoto, Y. Katsube, T. Ikawa, and Y. Katsura The Common Myelolymphoid Progenitor: A Key Intermediate Stage in Hemopoiesis Generating T and B Cells J. Immunol., October 1, 2002; 169(7): 3519 - 3525. [Abstract] [Full Text] [PDF] M. G. Manz, T. Miyamoto, K. Akashi, and I. L. Weissman Prospective isolation of human clonogenic common myeloid progenitors PNAS, September 3, 2002; 99(18): 11872 - 11877. [Abstract] [Full Text] [PDF] C. Voisine, F.-X. Hubert, B. Trinite, M. Heslan, and R. Josien Two Phenotypically Distinct Subsets of Spleen Dendritic Cells in Rats Exhibit Different Cytokine Production and T Cell Stimulatory Activity J. Immunol., September 1, 2002; 169(5): 2284 - 2291. [Abstract] [Full Text] [PDF] M. R. Comeau, A.-R. Van der Vuurst de Vries, C. R. Maliszewski, and L. Galibert CD123bright Plasmacytoid Predendritic Cells: Progenitors Undergoing Cell Fate Conversion? J. Immunol., July 1, 2002; 169(1): 75 - 83. [Abstract] [Full Text] [PDF] Y. Wang, Y. Zhang, H. Yoneyama, N. Onai, T. Sato, and K. Matsushima Identification of CD8alpha +CD11c- lineage phenotype-negative cells in the spleen as committed precursor of CD8alpha + dendritic cells Blood, June 28, 2002; 100(2): 569 - 577. [Abstract] [Full Text] [PDF] R. J. Steptoe, J. M. Ritchie, and L. C. Harrison Increased Generation of Dendritic Cells from Myeloid Progenitors in Autoimmune-Prone Nonobese Diabetic Mice J. Immunol., May 15, 2002; 168(10): 5032 - 5041. [Abstract] [Full Text] [PDF] T. Graf Differentiation plasticity of hematopoietic cells Blood, May 1, 2002; 99(9): 3089 - 3101. [Full Text] [PDF] A. D. McLellan, M. Kapp, A. Eggert, C. Linden, U. Bommhardt, E.-B. Brocker, U. Kammerer, and E. Kampgen Anatomic location and T-cell stimulatory functions of mouse dendritic cell subsets defined by CD4 and CD8 expression Blood, March 15, 2002; 99(6): 2084 - 2093. [Abstract] [Full Text] [PDF] P. Martin, S. R. Ruiz, G. M. del Hoyo, F. Anjuere, H. H. Vargas, M. Lopez-Bravo, and C. Ardavin Dramatic increase in lymph node dendritic cell number during infection by the mouse mammary tumor virus occurs by a CD62L-dependent blood-borne DC recruitment Blood, February 15, 2002; 99(4): 1282 - 1288. [Abstract] [Full Text] [PDF] G. M. del Hoyo, P. Martin, C. F. Arias, A. R. Marin, and C. Ardavin CD8alpha + dendritic cells originate from the CD8alpha - dendritic cell subset by a maturation process involving CD8alpha , DEC-205, and CD24 up-regulation Blood, February 1, 2002; 99(3): 999 - 1004. [Abstract] [Full Text] [PDF] L. Wu, A. D'Amico, H. Hochrein, M. O'Keeffe, K. Shortman, and K. Lucas Development of thymic and splenic dendritic cell populations from different hemopoietic precursors Blood, December 1, 2001; 98(12): 3376 - 3382. [Abstract] [Full Text] [PDF] D. Izon, K. Rudd, W. DeMuth, W. S. Pear, C. Clendenin, R. C. Lindsley, and D. Allman A Common Pathway for Dendritic Cell and Early B Cell Development J. Immunol., August 1, 2001; 167(3): 1387 - 1392. [Abstract] [Full Text] [PDF] D. Traver, T. Miyamoto, J. Christensen, J. Iwasaki-Arai, K. Akashi, and I. L. Weissman Fetal liver myelopoiesis occurs through distinct, prospectively isolatable progenitor subsets Blood, August 1, 2001; 98(3): 627 - 635. 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