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IMMUNOBIOLOGY
From the Walter and Eliza Hall Institute of Medical
Research, P.O. Royal Melbourne Hospital, Victoria,
Australia; and the Institute for Medical Microbiology,
Immunology and Hygiene, Technical University of Munich,
Germany.
The antigen-presenting dendritic cells (DCs) found in mouse
lymphoid tissues are heterogeneous. Several types of DCs have been
identified on the basis of the expression of different surface molecules, including CD4, CD8 The antigen-presenting dendritic cells (DCs)
constitute a system of hemopoietic cells that are sparsely but widely
distributed. Variation in their tissue distribution and in their
surface phenotype indicates the existence of distinct subpopulations of
DCs.1-3 Several DC subsets differing in surface markers
and detailed function have been identified.3-8 It has been
suggested that these DC subpopulations are products of precursors of
different hemopoietic lineages. We proposed the existence of 2 different DC lineages, namely, the myeloid- and the lymphoid-related
lineages. Murine CD8 Recently, we have shown that murine DCs are more heterogeneous than
just this CD8 The recent identification of murine bone marrow (BM) clonogenic
lymphoid- and myeloid-committed progenitors14,15 made it possible to examine the lineage origin of the different DC populations. In this study, we have examined the potential of the committed lymphoid
and myeloid progenitors of BM and thymus for their potential to
generate different DC populations and have compared the developmental kinetics of each DC population derived from these different precursors. We found that both the common lymphoid precursors (CLPs) and the common
myeloid precursors (CMPs) were capable of producing all thymic and
splenic DC populations. The more committed precursors, namely, the
CD4low lymphoid precursors of thymus16,17 and
the granulocyte and macrophage precursors (GMPs) of BM, were also able
to produce all DC populations. However, the DC subpopulation balance
and the kinetics of development varied with the precursor used. This study demonstrates that DCs can be produced from both lymphoid- and
myeloid-committed precursor populations. However, in contrast to our
previous assumption that CD8 Mice
Antibodies
Isolation of precursor populations The early intrathymic lymphoid-precursor population (CD3 CD8CD4lowc-kit+CD25Thy-1low)
was purified by means of a procedure described
previously.20 The BM precursors were isolated by
procedures modified from these described by Kondo et al14
and Akashi et al.15 The CLP population from mouse
BM was purified by immunomagnetic bead depletion of lineage
marker-positive cells, followed by enrichment sorting for
Sca-1low/+ cells. These enrichment-sorted cells were
stained with anti-Thy-1.1-FITC, anti-c-kit-APC, anti-Sca-1-Alexa
594, and anti-IL-7R -biotin, followed by PE-avidin as the second
stage. CLPs were then sorted as
IL-7R+Sca-1intc-kitint
Thy-1.1 cells on a FACstar-Plus instrument (Becton
Dickinson, San Jose, CA). The myeloid-committed precursor populations
from BM were isolated by first depleting lineage marker-positive cells
by means of immunomagnetic beads. The remaining cells were then stained with goat antirat immunoglobulin-Texas Red and anti-c-kit-APC and
were then enrichment sorted for linc-kit+
cells. The enrichment-sorted cells were then stained with
anti-FcR II/III-FITC, anti-c-kit-APC, anti-IL-7R-Alexa 594, anti-Sca-1-Alexa 594, and anti-CD34-biotin, followed by PE-avidin.
The CMP population was sorted as
FcRII/IIIlowCD34+c-kit+Sca-1IL-7R
cells; the GMP population was sorted as
FcRII/III+CD34+c-kit+Sca-1IL-7R
cells. The purity of sorted cells was determined by reanalyzing a small
sample of the collected cells and was usually greater than
97%.
In vivo assays for DC production by different precursor populations To examine the capacity for DC production, purified precursor cells (1 to 4 × 104) from C57BL Ly 5.2 mice were intravenously (IV) injected into lethally irradiated (5.5 Gy twice with a 3-hour interval) C57BL Ly 5.1 recipients, along with 5 × 104 recipient type Ly 5.1 unfractionated BM cells to ensure mouse survival. At various times after precursor transfer, the thymus and spleen of recipients were collected, and DCs were enriched from these tissues by means of a procedure described elsewhere.3 These DC-enriched preparations were then stained in 4 colors with fluorescent-conjugated antibodies to Ly 5.2 to reveal donor-derived cells, together with conjugated antibodies to other markers expressed by DCs, including the pan-DC markers CD11c and MHC class II and the DC subset-specific markers CD4, CD8, DEC-205,
and CD11b. Donor-derived DCs were revealed by electronic gating for
Ly5.2+CD11c+ cells during flow cytometric
analysis. The expression of other DC markers by these donor-derived DCs
was further examined, and the proportion of the individual
donor-derived DC subpopulations was then determined.
Mixed leukocyte cultures for assaying DC function The culture system has been described in full elsewhere.21 Briefly, various numbers of purified donor-derived splenic DCs were cultured in the presence of IL-2 (20 ng/mL) with 20 000 purified CD4+ or CD8+ T cells from lymph nodes of Balb/c mice. A 6-hour pulse of 3H-thymidine (3H-TdR) was given at day 3 of culture and label-incorporated into cellular DNA determined by liquid scintillation counting, as a measurement of CD4 or CD8 T-cell proliferation. Background incorporation in the absence of DCs was always fewer than 1000 cpm.Analysis of IL-12 production by DCs The procedures were similar to those described elsewhere.22 Purified splenic DC populations (0.5 × 106/mL) were cultured in duplicate in 96-well round-bottomed plates in a final volume of 100 µL with an IL-12 stimulus (100 U/mL murine recombinant (r) IL-4 (a gift from Immunex, Seattle, WA); 200 U/mL murine rGM-CSF (a gift from Immunex); 20 ng/mL rat recombinant interferon (IFN)- (bioactive in mice,
Pepro Tech, Rocky Hill, NJ); and 0.5 µM fully
phosphorothioated (CpG) CpG1668 oligonucleotide (synthesized by GeneWorks, Adelaide, Australia). After an 18- to 23-hour culture, the supernatant was collected, separated from cells
by centrifugation, and stored at  70°C until analysis. Aliquots of
the DC culture supernatants were assayed by 2-site enzyme-linked immunosorbent assay (ELISA). Briefly, 96-well polyvinyl chloride microtiter plates (Dynatech Laboratories) were coated with the purified capture monoclonal antibody, namely, R2-9A5 (anti-IL-12 p70)
(the hybridoma was obtained from ATCC, Manassas, VA). Cytokine binding
was detected with the biotinylated detection monoclonal antibody,
namely, C17.8 (anti-IL-12 p40) (hybridoma provided by L. Schofield,
The Walter and Eliza Hall Institute of Medical Research). The readout
was then obtained by using streptavidin-horseradish peroxidase
conjugate (Amersham Pharmacia-Biotech, Buckinghamshire, United
Kingdom) and a substrate solution containing 548 µg/mL 2,2'-azino-bis (3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS) (Sigma-Aldrich, St Louis, MO) and 0.001% hydrogen peroxide
(Ajax Chemicals, Auburn, Australia) in 0.1 M citric acid, pH
4.2, followed by scanning the optical density at 405 to 490 nm.
BM-derived precursors generate all DC populations in thymus and in spleen Our previous studies demonstrated the existence of different DC populations in mouse thymus and spleen.3 We have identified at least 2 thymic DC populations, namely, CD4CD8+ and
CD4CD8; and 3 splenic DC populations,
namely CD4+CD8,
CD4CD8, and
CD4CD8+. We have also shown that all 3 splenic DC populations could be generated on transfer of BM cells into
irradiated recipients.13 We now extend this to show that
all DC populations present in normal mouse thymus and spleen can be
generated by precursors in BM (Figure 1).
However, at the earlier times (2 weeks) after BM transfer, the highest
level and proportion of CD4CD8+ DCs were
generated in spleen, whereas the generation of
CD4+CD8 DCs, the major DC population in
normal mouse spleen, reached its peak much later (4 weeks). The
proportion of each splenic DC population generated by BM did not match
the proportions found in the normal mouse spleen until 4 to 8 weeks
after BM transfer13(Table 1; Kamath et
al13(Fig 8)).
The BM-derived splenic DCs can function as mature antigen-presenting cells To determine whether the DCs produced in the irradiated recipients by the transferred BM precursors were mature and functional antigen-presenting cells, we examined these BM-derived DCs for their ability to stimulate T-cell proliferation in an allo-MLR assay. As shown in Figure 2, when compared with normal splenic DCs, the BM-derived total splenic DCs and CD8+ DC subset, isolated after BM transfer, stimulated
proliferation of both CD4+ and CD8+ allogeneic
T-cells with similar, if not better, efficiency compared with normal
total splenic DCs and CD8+ DCs. This indicated that
these BM-derived splenic DC populations were mature and did not
require further maturation to become functional antigen-presenting
cells.
The splenic CD4 CD8+ DCs generated at early time points
(2 weeks) after BM transfer were identical with normal steady-state
splenic CD4CD8+ DCs. To determine whether
these early CD4CD8+ DC products of BM were
functional, we used an ELISA assay to determine their ability to
produce IL-12, as normal splenic CD4CD8+
DCs have a high capacity to produce IL-12 p70 (the bioactive form).4,5,7 As shown in Figure
3, when activated by a combination of
stimuli including IL-4, GM-CSF, IFN-, and CpG, the BM-derived splenic CD4CD8+ DCs formed early after BM
transfer produced an amount of IL-12 p70 similar to that produced by
normal splenic CD4CD8+ DCs. By this
criterion, the splenic CD4CD8+ DCs
produced in large numbers soon after BM transfer were functional DCs.
DC production by lymphoid-restricted precursors Our previous studies have shown that the early intrathymic lymphoid precursors (CD4low precursors) have the potential to generate DCs.9,11,23 To extend this to BM, we compared the capacity for DC production by the intrathymic CD4low precursors with that of the BM CLPs. Purified CD4low precursors (2 to 3 × 104) and BM CLPs (1 to 2 × 104) from C57BL Ly 5.2 mice were IV injected into irradiated C57BL Ly 5.1 recipients. At 1 to 4 weeks after transfer, DCs were enriched from the thymus and spleen of the recipients and stained for Ly 5.2, together with the DC markers CD11c, CD4, CD8, and DEC-205. Donor-derived DCs were revealed by gating for Ly 5.2+CD11c+ cells during flow-cytometric analysis, and the donor-derived DC subpopulations were determined on the basis of their expression of CD4, CD8, and DEC-205, as shown in Figure 1. The total number of donor-derived DCs and the total number of each donor-derived DC subpopulation in thymus and spleen were calculated and are shown in Table 2. Both the intrathymic CD4low and BM CLP precursor populations were capable of repopulating thymic and splenic DC populations, as shown in Table 2 and Figure 4. On a per cell basis, the BM CLPs were much more potent than the intrathymic CD4low precursors in DC production. However, the production of DCs by both these lymphoid precursors was transient, with a maximum in both thymus and spleen at 2 weeks after precursor transfer (Table 2; Figure 4B). The DC production then declined rapidly and was almost undetectable by 4 weeks (Table 2; Figure 4B). In contrast, after the initial 2-week peak and partial decline, DC production by BM cells13 (Table 1) was maintained at a constant level for at least 8 weeks after BM cell transfer, along with the maintenance of other hemopoietic lineages (data not shown). These results were expected, since the lymphoid-restricted precursors have very little self-renewal capacity and therefore gave a transient DC reconstitution, whereas the multipotent hemopoietic stem cells (HSCs) contained in the BM have self-renewal capacity and therefore gave a long-term repopulation of DCs.
The major DC product of both lymphoid-restricted precursors was
CD4 DC production by myeloid-committed precursors Although we had considered the CD8 DC populations
myeloid derived, direct evidence had not been available. A recent study by Traver et al18 reported that both CD8+
and CD8 DCs could be generated by BM CMPs. However, it
was not clear whether all 3 splenic DC populations could be generated
from CMPs and whether these DCs were generated with similar kinetics.
Accordingly, we examined the capacity for DC production by the BM CMPs
and their more restricted downstream product, the GMPs. Purified CMPs and GMPs from C57BL/6 Ly 5.2 mice were injected IV into lethally irradiated Ly 5.1 recipients. DC production in the thymus and spleen by
these precursors was analyzed 1 to 4 weeks after precursor transfer. As
shown in Figure 5 and Table 3, both CMPs
and GMPs were capable of producing all thymic and splenic DC
subpopulations, including the CD8+ DCs. And as expected,
the splenic CD4+CD8 and
CD4CD8 DCs derived from both precursor
populations also expressed the myeloid marker CD11b, but the
CD4CD8+ DC progeny did not (data not
shown). However, the capacity for DC production by GMPs was rather poor
compared with CMPs, and that of CMPs was substantially less than for
CLPs (Tables
2-3). The
DC production by both myeloid precursor populations was transient, indicating a lack of self-renewal capacity. Similarly to what occurs in
the lymphoid precursors, the production of the
CD4CD8+ DC population in the spleen by
these myeloid precursors reached a peak 2 weeks after cell transfer
(Figure 5 and Table 3). However, unlike the lymphoid precursors, the
production of the CD4+CD8 DCs reached a
peak level at 3 weeks after precursor transfer, when the number of the
CD4+CD8 DCs was almost the same as that of
CD4CD8+ DCs at their peaks. These results
indicated that the committed myeloid precursors were capable of
generating all thymic and splenic DC populations. However, on a
cell-for-cell basis, the myeloid precursors were less efficient at DC
production than the lymphoid-restricted precursors, and they produced a
different balance of DC subtypes.
Production of IL-12 p70 by
CD8 + DCs of mouse spleen have been shown to
have the greatest potential to produce the bioactive p70 form of
IL-12.4,5,7 To determine if the CD8+ DCs
derived from CLPs and CMPs were equivalent in this respect, the
CD8+ DC progeny of the isolated precursors were sorted
from separate groups of recipient mice and assayed for IL-12 p70
production side by side under optimized culture
conditions.7 In 3 separate experiments, the production of
IL-12 p70 by CD8+ DCs (0.5 × 106/mL) was
42.3 to 49.3 ng/mL for CLP-derived DCs, and 43.8 to 53.1 ng/mL for
CMP-derived DCs, compared with 26.0 to 33.1 ng/mL for CD8+ DCs isolated from normal mouse spleen. Thus both
myeloid- and lymphoid-derived CD8+ DCs share this common
function, with the conditions in the irradiated recipient promoting the
potential for IL-12 production.
DCs are specialized for the collection, transport, processing, and
presentation of antigen to T lymphocytes. Although all DCs share these
biological features, DCs have been found to be heterogeneous in surface
phenotype and in biological functions.1,2,24,25 Particularly important is the ability of different subtypes to produce
different cytokines and so induce different T-cell
responses.4,5,7,26-28 Are these functionally distinct DC
subtypes simply activation or maturation states of a single DC lineage,
or are they products of quite separate developmental lineages? Our
recent studies on the relative maturation state and developmental
kinetics of the 3 splenic DC populations,
CD4+CD8 The starting point of the lymphoid DC versus myeloid DC concept was our
finding that an early lymphoid-restricted T-cell precursor in mouse
thymus was able to produce CD8 Our results agree with the recent studies of Manz et al19 in reinforcing the originally surprising concept that a lymphoid-restricted precursor population still has the capacity to produce DCs; this is now extended to include the lymphoid-restricted precursors of BM, which are even more efficient at DC production in our adoptive transfer system. We have found that these lymphoid-restricted precursors can also generate DCs in culture (unpublished data, March 2000). Since these lymphoid precursors are more efficient at DC production than myeloid-restricted precursors, trace contamination with the latter cannot explain our results. Since these lymphoid precursors give a fast and transient repopulation of DCs along with the lymphoid cells, a characteristic of committed precursors, rather than the prolonged reconstitution of all lineages characteristic of multipotent stem cells, trace contamination with the latter cannot explain our results. Separate committed DC precursors and lymphoid precursors with identical surface markers within our lymphoid-restricted population remains a possibility, but then these DC precursors would have to be separate specialized subsets of lymphoidlike DC precursors with reconstitution characteristics different from those of myeloidlike DC precursors. The simplest hypothesis at this stage is that individual lymphoid-restricted precursor cells retain a capacity to form DCs, even though they have lost the capacity to form most myeloid cells. Our original hypothesis was that lymphoid-precursors would produce only
CD8 The key piece of evidence missing at the time of our original
hypothesis was the nature of the DCs produced by the myeloid-restricted precursors; they were assumed to generate only CD8 Our results are therefore in accordance with the Stanford
laboratory18,19 in indicating that all DC subtypes as
determined by surface phenotype can be of lymphoid- or
myeloid-precursor origin. As assessed by IL-12 p70 production, they are
also equivalent in function. Although in our studies the lymphoid
precursors are more efficient at DC production on a per cell basis, the
large excess of myeloid precursors in BM makes it likely that most
splenic DCs are of myeloid-precursor origin. However, local
environmental influences could greatly alter this calculated balance.
In addition, it is not clear that all immediate DC precursors are
accounted for by the CLP, CMP, and GMP BM populations, since these
precursors were selected and purified on the basis of assays for
production of hemopoietic lineages other than DCs. Our data and our
preliminary studies suggest that DC precursors other than CLPs and CMPs
may exist in the BM. The total number of CD8 Our results extend the data from our previous studies and from the
recent studies of the Stanford laboratory by following the kinetics of
development of each DC subtype, particularly the development of the
major CD4+CD8 Overall, our results point to a substantial developmental flexibility, in terms of DC subtype production, at the level of the early hemopoietic precursors. The points downstream of these precursors where the DC sublineages diverge and become more fixed, and the factors determining this divergence, now need to be elucidated.
The authors wish to thank Dr F. Battye, D. Kaminaris, V. Lapatis, and J. Parker for their assistance with flow cytometry.
Submitted May 9, 2001; accepted July 31, 2001.
Supported by the National Health and Medical Research Council, Australia, and by a Deutsche Krebshilfe fellowship (H.H.). L.W. is a Clinical Investigator of Cancer Research Institute (New York, NY). The Wellcome Trust provided funds for cell sorting instruments.
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: Li Wu, The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Victoria. 3050, Australia; e-mail: wu{at}wehi.edu.au.
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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]
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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]
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S. L. Nutt, D. Metcalf, A. D'Amico, M. Polli, and L. Wu Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors J. Exp. Med., January 18, 2005; 201(2): 221 - 231. [Abstract] [Full Text] [PDF]
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 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]
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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]
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A. Dakic, Q.-x. Shao, A. D'Amico, M. O'Keeffe, W.-f. Chen, K. Shortman, and L. Wu Development of the Dendritic Cell System during Mouse Ontogeny J. Immunol., January 15, 2004; 172(2): 1018 - 1027. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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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]
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A. D. Edwards, D. Chaussabel, S. Tomlinson, O. Schulz, A. Sher, and C. Reis e Sousa Relationships Among Murine CD11chigh Dendritic Cell Subsets as Revealed by Baseline Gene Expression Patterns J. Immunol., July 1, 2003; 171(1): 47 - 60. [Abstract] [Full Text] [PDF]
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C. Vasu, R.-N. E. Dogan, M. J. Holterman, and B. S. Prabhakar Selective Induction of Dendritic Cells Using Granulocyte Macrophage-Colony Stimulating Factor, But Not fms-Like Tyrosine Kinase Receptor 3-Ligand, Activates Thyroglobulin-Specific CD4+/CD25+ T Cells and Suppresses Experimental Autoimmune Thyroiditis J. Immunol., June 1, 2003; 170(11): 5511 - 5522. [Abstract] [Full Text] [PDF]
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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]
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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]
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D. Haribhai, D. Engle, M. Meyer, D. Donermeyer, J. M. White, and C. B. Williams A Threshold for Central T Cell Tolerance to an Inducible Serum Protein J. Immunol., March 15, 2003; 170(6): 3007 - 3014. [Abstract] [Full Text] [PDF]
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G. Schiavoni, F. Mattei, P. Sestili, P. Borghi, M. Venditti, H. C. Morse III, F. Belardelli, and L. Gabriele ICSBP Is Essential for the Development of Mouse Type I Interferon-producing Cells and for the Generation and Activation of CD8{alpha}+ Dendritic Cells J. Exp. Med., December 2, 2002; 196(11): 1415 - 1425. [Abstract] [Full Text] [PDF]
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I. Ferrero, W. Held, A. Wilson, F. Tacchini-Cottier, F. Radtke, and H. R. MacDonald Mouse CD11c+ B220+ Gr1+ plasmacytoid dendritic cells develop independently of the T-cell lineage Blood, September 26, 2002; 100(8): 2852 - 2857. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
