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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2001-11-0097.
IMMUNOBIOLOGY
From the Dendritic Cell Laboratory, Mater Medical
Research Institute, Mater Misericordiae Hospitals, South Brisbane,
Australia; Miltenyi Biotec GmbH, Bergisch Gladbach,
Germany.
Dendritic cells (DCs) are key antigen-presenting cells for
stimulating immune responses and they are now being investigated in
clinical settings. Although defined as lineage-negative
(Lin Dendritic cells (DCs) are specialist
antigen-presenting cells that originate from the bone marrow and play
critical roles in the initiation and direction of immune
responses.1,2 They are being investigated in cancer
biology, transplantation, and autoimmunity. The definition of a DC, to
date, has been mainly a functional one.2 The ability of
DCs to take up, process, and present antigens to stimulate T (and B)
lymphocytes is accompanied by certain, less consistent, phenotypic and
morphologic features. DCs lack certain lineage (Lin)-specific markers
and express high levels of major histocompatibility complex (MHC) class
II molecules; thus, the phenotypic definition of DC as
Lin Human blood DC preparations contain several phenotypically and
functionally distinct subpopulations.8,9 Their
constitution, function, and lineage of origin still require
clarification. The original "myeloid"
CD11c+CD123lo DC subset is now contrasted with
the CD11c Knowledge of the relative contributions of the DC subsets to a defined
Lin Monoclonal and polyclonal antibodies used in the study are
listed in Table 1.
Cell purification
For T-cell purification, PBMCs were fractionated by incubation with
neuraminidase-treated sheep red blood cells followed by separation of
the rosetting (ER+) and nonrosetting (ER For generation of monocyte-derived DCs (MoDCs), the nonrosetting population was cultured at 0.3 × 106 CD14+ monocytes/mL in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF; 200 U/mL, Sandoz-Pharma, Basel, Switzerland) and interleukin 4 (IL-4; 50 U/mL, Sigma, St Louis, MO) for 5 days.21 Cell staining Cells were incubated with mAb according to the manufacturer's instructions, or at 5 to 20 µg/mL in 2% fetal calf serum (FCS) in phosphate-buffered saline (PBS), or in hybridoma culture supernatant for 20 to 60 minutes at 4°C. Cells were washed in 2% FCS in PBS. Unconjugated mAbs were detected with the appropriate conjugated secondary detection reagents diluted in 2% FCS in PBS. For phenotypic analysis, following staining the cells were washed and fixed with 1% paraformaldehyde prior to analysis on a FACS Calibur cytometer (Becton Dickinson). For cell survival studies, unfixed cells were analyzed, and propidium iodide (PI; 3 µg/mL) was used to identify dead cells. Cytoplasmic staining, using "Fix & Perm" (Caltag, Burlingame, CA), for langerin was done on PBMCs by 4-color flow cytometry using biotinylated antilangerin mAb (CD207, DCGM-4) detected with streptavidin-peridinin chlorophyll protein (PerCp). DCs were identified as surface-labeled Lin mAb-FITC /HLA-DR-APC+ events, and DC subsets
were identified with the appropriate PE conjugates.
DC culture Sort-purified LinCD11c+
(± CD16+ cells) or LinCD11c
cells were incubated overnight at 106 cells/mL in RPMI 1640 with 10% FCS, 10 ng/mL IL-3 (Gibco BRL, Grand Island, NY)
and 200 U/mL GM-CSF, or were cocultured in the absence of cytokines
with allogeneic CD3+ T cells at a 1:1 ratio.
Allogeneic MLRs Allogeneic mixed leukocyte reactions (MLRs) were established using various numbers of each Lin subset cultured in
triplicate in round-bottom 96-well tissue culture plates (Costar,
Acton, MA) with 105 freshly isolated allogeneic T
cells, at 37°C in 5% CO2 for 5 days. T-cell
proliferation was measured by the uptake of
[3H]-thymidine (1 µCi/well [0.037 MBq/well]; 6.7 Ci/mM [248 MBq/mM]; Amersham, Buckinghamshire, United
Kingdom), which was added 18 hours prior to harvesting. Cells were
harvested onto glass fiber filter paper with an automated harvester
(TomTec Mach III, Hamden, CT) and [3H]-thymidine
incorporation was measured by liquid scintillation spectroscopy
(Wallac, Turku, Finland). Responses are reported as mean
cpm ± SEM for triplicate wells.
Analysis of the composition of Lin PBMC preparations using
either CD16 or CD56 mAb to deplete natural killer (NK) cells, the
latter with a view to studying the CD16+ DC
population.5,12 The resulting CD16- and CD56-depleted Lin preparations were examined for purity, assessed by
reactivity with FITC-conjugated sheep anti-mouse immunoglobulin
(FITC-SAM) to detect contaminating Lin+ cells. The majority
(75% ± 25.8% SD, n = 14) of cells within both types of
Lin preparations were Lin (R1 in Figure
1) or weakly fluorescent (within the
second decade of fluorescence intensity, R2 in Figure 1). The remaining
strongly labeled cells were considered to be contaminating
Lin+ cells (R3, Figure 1A,F).
The composition of the Lin As expected, Lin CD123, CD1b/c, CD16, BDCA-3, and CD34 subdivide the
Lin ,
CD123lo, and CD123hi subpopulations are present
in Lin preparations.9 Furthermore,
CD34+ cells have been documented as components of
LinHLA-DR+ preparations.20 We,
therefore, examined the relative frequency and the level of expression
of HLA-DR and CD11c by each of the 5 Lin subsets defined
using these reagents (CD16, CD1b/c, BDCA-3, CD123, and CD34).
Initial 2-color analysis confirmed that each of the 5 subsets was
present in the Lin
Further 3-color analysis of a series of CD56-depleted Lin
Having positively defined 5 populations, additional triple-labeling
studies were undertaken to clarify that they were nonoverlapping subsets. Thus, sort-purified Lin
The 5 Lin HLA-DR+
populations for their expression of markers reported to be expressed by
DC subsets. Lin preparations were labeled with FITC- or
PE-SAM followed by HLA-DR-PE-Cy5, and the
LinHLA-DR+ cells (ie,
HLA-DR+ cells within R1 and R2, Figure 1) were sorted. They
were then labeled with one of the 5 PE- or FITC-conjugated subset
markers and one of a panel of PE- or FITC-conjugated mAbs or
isotype-matched controls (Table 3). An
analysis of CD14hi monocytes and immature MoDCs was also
performed for comparative purposes. Of note, cutaneous lymphocyte
antigen (CLA), a homing receptor for skin that has previously
been reported to be widely expressed by DCs,15,23 was not
detected on the CD16+ population and only minimally
expressed on the MoDCs. In contrast, all other populations expressed
CLA either homogeneously (CD1b/c, BDCA-3, CD123) or heterogeneously
(CD34 and CD14). Additionally, CD2 expression was limited to the
CD1b/c+ population, a small and variable proportion of the
CD123hi and CD34+ subsets, and a small subset
of CD14hi monocytes. CD64 expression was restricted to the
CD1b/c subset and the CD14hi monocytes. A small proportion
of each LinHLA-DR+CD11c+
subpopulation expressed CD56, in contrast to CD7 expression, which was
confined to a subset of the CD123hi population.
The 5 Lin HLA-DR+ subsets (Figure
4; Table 3).
CD85j (ILT-2/LIR1/MIR7) is expressed widely by leukocytes including
myeloid DCs. CD85j expression by CD16-depleted Lin The expression of CD85k (ILT-3, mAb ZM3.8), CD85d (ILT-4, mAb 42D1),
and CD85a (ILT-5, mAb 7H5) by the 5 populations is summarized in Table
3. Again, the CD34+ population lacked expression of these 3 ILT molecules. The CD16 and CD1b/c subsets expressed varying levels of
each. The BDCA-3 population expressed minimal levels of ILT-3, but none
of the other molecules. The CD123hi population expressed
ILT-3 at levels equivalent to the CD1b/c subset, but lacked expression
of ILT-4 and ILT-5. Monocytes, as expected, expressed all the CD85
molecules tested at similar densities, whereas MoDCs expressed profiles
intermediate to the CD16+ and CD1b/c+
Lin C-type lectin expression by the 5 Lin HLA-DR+ by the 5 LinHLA-DR+ subsets was examined in light of
their potential to identify DC subpopulations. In contrast to MMR,
DC-SIGN, and langerin, which were not detected on any of the
LinHLA-DR+ subsets, DEC-205 was present on
all the subsets (Table 3). Differential levels of DEC-205 expression
were noted, with the BDCA-3+ subset expressing the highest
levels, followed by the CD123hi, CD1b/c+, and
CD34+ subsets, which expressed equivalent levels. The
CD16+ subset expressed the lowest levels. Fresh monocytes
expressed DEC-205 at a level similar to the CD1b/c+,
CD123hi, and CD34+ subsets. Notably, MoDCs
expressed lower levels of DEC-205 than the monocytes from which they
were derived. Whereas MMR and DC-SIGN were absent from all
Lin populations (confirmed by reverse-transcription
polymerase chain reaction, data not shown) and CD14hi
monocytes, both of these lectins were expressed by MoDCs. Langerin was
not found on the surface of any of the freshly purified DC populations
examined and cytoplasmic levels were, at most, marginally positive
(Table 3). Langerin was induced on a subset of
CD11c+Lin cells after 18 hours of in vitro
culture (in the absence of cytokines),19 confirming the
specificity of antibody staining, but the ability to discriminate the
DC subsets was lost after in vitro culture and this aspect was not
pursued further.
Disparate CD40 and CD86 expression on freshly purified
Lin HLA-DR+ subsets or monocytes
expressed detectable levels of cell surface CD80, in contrast to MoDCs,
which uniformly expressed low levels (Table 3).
Decreased viability of the CD123+ and CD16+ subsets following in vitro culture Differences between the CD11c+ and CD123+ subsets in their survival in vitro have been described.24 Therefore, we examined the survival of the DC subsets following 18 hours of culture. Cultured CD11c+ DCs have been observed to up-regulate cell surface CD123, such that gating CD11c+ and CD11c populations becomes difficult. Furthermore,
following 18 hours of culture, BDCA-3 was expressed by an increased
proportion of CD11c+ cells and was induced on a subset of
CD123+ cells.18 Thus, to facilitate subset
tracking in these studies, LinCD11c+ and
CD11c subsets were sorted prior to culturing. Following
18 hours in the presence of GM-CSF and IL-3, or allogeneic T cells, the
survival of the CD11c+CD16
(CD1b/c+ and BDCA-3+ populations),
CD11c+CD16+,
CD11cCD34 (CD123+ population)
and CD11c CD34+ populations was examined.
Even in the presence of GM-CSF and IL-3, cytokines reported to increase
the survival of the CD11c+ and CD123+ cells,
respectively,24 significant cell death occurred in both the CD11c+ and CD11c cultures. Comparison of
the relative proportion of CD16+ and CD34+
cells in these cultures indicated that the
CD11c+CD16+ and CD123+ populations
had the poorest survival (Figure 6A).
Thus, whereas the freshly sorted CD11c+ preparations
contained 68% (± 6.6% SD; n = 4) CD16+ cells,
following culture, this decreased to 31% (± 6.7%; n = 4) of
viable (based on forward- and side-scatter characteristics) CD11c+ cells. To demonstrate that the loss of
CD16+ cells was due to cell death rather than the loss of
cell surface CD16 expression, CD11c+ (CD16+
inclusive) and CD11c+CD16 populations were
sort purified and cultured as described above. As can be seen in Figure
6B, the CD11c+ (CD16+ inclusive) cultures
contained an increased proportion of PI+ dead cells (46%)
as compared to the CD11c+CD16 cultures
(13%). Sort-purified CD11c+CD16+ cells were
also examined and exhibited equally poor survival in culture (data not
shown). Similarly, the relative frequency of CD34+ cells in
CD11c populations following 18 hours culture increased
(from 28% to 71%) reflecting a proportionately greater decrease in
the number of CD123+ cells. Addition of allogeneic T cells
to the DC cultures had no effect on the relative proportion of any of
the subsets examined (data not shown). Thus, as previously documented,
DCs survive poorly in vitro, with the CD123+ and the
CD11c+CD16+ subsets having the poorest survival
rate of the 4 subsets examined.
In vitro induction of activation-associated molecules on
Lin CD11c+ (including
CD16+) and CD11c subsets were sorted and
cultured as described above, and the expression of CMRF-44, CMRF-56,
and CD83 was examined on the CD11c+CD16 and
CD11c+CD16+ subsets (Figure
7A) and the
CD11cCD34+ (ie, CD34+)
and CD11cCD34 (ie,
CD123+) populations (Figure 7B). The cultured
CD11c+CD16 cells expressed uniformly high
levels of each of CMRF-44, CMRF-56, and CD83. The level of expression
of these antigens was not increased further on this population
following coculture with allogeneic T cells. CMRF-44, CMRF-56, and CD83
were induced on the CD11c+CD16+ population;
however, the levels of expression of CMRF-44 and CMRF-56 were
distinctly lower than that of the CD11c+CD16
subset, and only a proportion of the CD16+ cells expressed
CD83. Minimal additional increases in CMRF-44 and CMRF-56 staining of
both the CD16 and CD16+ subsets resulted
after coculture with T cells. Cultured CD123+
(CD11cCD34) cells expressed CMRF-44 and
CMRF-56 at levels comparable to the
CD11c+CD16 population, whereas CD83
expression was much less. However, coculture with allogeneic T cells
induced higher levels of all 3 molecules on the CD123+
population. Finally, only a very small proportion of CD34+
cells was induced to express CMRF-44 or CMRF-56, which was slightly increased by T-cell coculture. CD83 was not detected on the
CD34+ cells in either culture condition.
Allostimulatory capacity of Lin subsets to induce T-cell proliferation in allogeneic
MLRs. Monocytes and MoDCs were included as reference populations. For
comparative purposes, the CD1b/c+ population was used as
the internal standard for each MLR. Each of the cell populations
tested exhibited some degree of allostimulatory capacity although
this was minimal for monocytes (Figure
8). Comparison of the blood
LinHLA-DR+ populations demonstrated clear
differences in their allostimulatory capacity; they were ranked
CD1b/c > CD16 > BDCA-3 > CD123 > CD34. The stimulator
dose/T-cell proliferative response curve for the BDCA-3 subset differed
significantly from the others, with an apparent early plateau. The
CD123+ populations were less effective stimulators of the
MLR and the CD34+ population was, as previously reported, a
weak but definite stimulator of an allogeneic MLR.
It is clear from recent differences in data reported in the
literature10,12,15 and from data presented at the 7th
LDAW16,19 that the cellular constitution of human blood DC
preparations varies considerably. The main factors likely to contribute
are the mAb mixtures used to select Lin The CD11c+ or myeloid blood DC population has been noted to be heterogeneous in our own16,25 and other studies.8,18 We show here that it includes the CD16+, CD1b/c+, and BDCA-3+ subpopulations. The CD16+ population comprised a large but variable (40%-80%) proportion of the CD11c+ subset. It expressed low levels of CD14 and CD33, was the only subset to lack CLA expression, and had heterogeneous but generally lower levels of cell surface HLA-DR. Curiously, the CD16+ population had the highest levels of CD86 and relatively high levels of CD40. An important feature of this cell population was its apparently poor viability in tissue culture with only 50% surviving 12 to 18 hours in 10% FCS/RPMI-1640, even in the presence of GM-CSF and IL-3. The CD1b/c+ population represents 20% to 50% of the CD11c+ population and was noted to express the highest levels of CD11c. It expresses low to negligible levels of CD14 but is clearly CD33+ and universally expresses high levels of cell surface HLA-DR. The correlation between increasing CD1b/c expression and increasing CD11c and HLA-DR expression in conjunction with heterogeneous CD40 expression is indicative of a population of cells undergoing differentiation. The BDCA-3 subpopulation is much smaller and accounts for 2% to 3% of the CD11c+ cells. Interestingly, its CD11c expression was consistently at the lower end of the range of the CD11c+ population. It lacked CD14 but was again clearly CD33+ with moderate to high levels of cell surface HLA-DR. Notably, these BDCA-3+ cells had lower levels of CD86 but expressed the highest levels of CD40 and DEC-205. As previously reported,9,10,25 the lymphoid or CD123hi DC population was readily distinguished from the myeloid CD11c+ DC population. However, we note that the CD11c+ population is unequivocally weakly CD123+ and that the expression of CD123 increases on in vitro culture, so that gating using this marker needs to be done carefully. Some heterogeneity in the CD123hi population was noted with differential expression of HLA-DR, CD40, CD2, and CD7. These studies emphasize the fact that
Lin In terms of the function of these subsets, we investigated their
expression of several relevant molecules and the classic definition of
DC function The MLR studies produced unequivocal results. The CD1b/c population invariably expressed high levels of the CD83, CMRF-44, and CMRF-56 antigens, which have been associated with DC differentiation or activation. Consistent with this, the CD1b/c subset was invariably the most potent allostimulatory cell population with the CD16+ population the next most effective stimulators. Curiously enough, these results were independent of the level of expression of the classic costimulator molecules CD80/CD86 and this may suggest that other costimulatory molecules such as OX40L, RANKL, or 41BBL may be involved. We confirmed that CD123hi DCs stimulate an allogeneic MLR9 as does the CD34+ cell population20 although the latter cells were the least effective stimulators in the absence of any prior in vitro differentiation. Clearly, further analysis of a number of different functional properties (including susceptibility to CD85-mediated inhibition) of these 5 potential DC subpopulations is required. The practicalities of this are daunting, but the major molecular and functional differences outlined in this work argue that each population may have to be addressed individually. It is even possible that certain subpopulations will be preferred for certain therapeutic applications. In our hands, the blood CD11c+ DCs38 and the CMRF-56+ DCs (Lopez et al, submitted manuscript) stimulate strong in vitro blood primary T-lymphocyte responses. Finally, although it is tempting to try and assign these
CD11c+ subsets to a theoretical DC
differentiation/activation pathway, we think it is premature to do so.
The CD11c+CD1b/c+ subset appears the most
activated phenotypically and functionally but whether it is derived
from a CD14+ precursor as previously
suggested15,18 requires confirmation. Although the
relationships of these subpopulations to accepted hematologic pathways
needs to be established, no direct correlation with MoDCs was observed.
The results nonetheless bring some clarity to the field and the
definition of these Lin
Submitted November 30, 2001; accepted June 24, 2002.
Prepublished online as Blood First Edition Paper, August 15, 2002; DOI 10.1182/blood-2001-11-0097.
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: Derek Hart, Dendritic Cell Laboratory, Mater Medical Research Institute, Mater Misericordiae Hospitals, South Brisbane, 4101, Australia; e-mail: dhart{at}mmri.mater.org.au.
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© 2002 by The American Society of Hematology.
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H. Fujiwara, F. El Ouriaghli, M. Grube, D. A. Price, K. Rezvani, E. Gostick, G. Sconocchia, J. Melenhorst, N. Hensel, D. C. Douek, et al. Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase Blood, April 15, 2004; 103(8): 3076 - 3083. [Abstract] [Full Text] [PDF]
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S. Turville, J. Wilkinson, P. Cameron, J. Dable, and A. L. Cunningham The role of dendritic cell C-type lectin receptors in HIV pathogenesis J. Leukoc. Biol., November 1, 2003; 74(5): 710 - 718. [Abstract] [Full Text] [PDF]
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N. Teleshova, I. Frank, and M. Pope Immunodeficiency virus exploitation of dendritic cells in the early steps of infection J. Leukoc. Biol., November 1, 2003; 74(5): 683 - 690. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
their ability to stimulate in an allogeneic MLR. Both the
CD123hi DCs and the BDCA-3+ subpopulation of
CD11c+ DCs express high levels of CD62L. It has been
suggested that CD62L may mediate the migration of the
CD123+ population directly from the blood via high
endothelial venules (HEVs) into lymphoid
tissues,
(TGF-
in combination with GM-CSF enhances the differentiation of neonatal cord blood stem cells into dendritic cells and macrophages.
J Leukoc Biol.
1992;52:274-281