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IMMUNOBIOLOGY
From the Department of Dermatology, Obstetrics and
Gynecology, and Virology, University of Würzburg, Würzburg,
Germany.
Mouse spleen contains CD4+, CD8 Bone marrow-derived dendritic cells (DCs) are
essential for the initiation of T-cell-based immune responses against
foreign antigen. DCs are present in the interstitial spaces and in
peripheral organs, including blood, skin, liver, and spleen but are
absent from immunoprivileged sites such as brain and testis. In the
periphery, DCs take up antigen and, under the stimulus of inflammatory
signals, migrate via the afferent lymph into regional lymph nodes where they stimulate antigen-specific T-cell responses. It is now well established that the phenotype of DCs may differ depending on their
tissue origin. For example, epithelial DCs in humans express CD1a, but
this marker is absent from other DC populations including those
circulating in blood1 and in dermis.2 More
recent findings have demonstrated a heterogeneity in DC populations
found within the same organ.3-8 Part of this heterogeneity
may be explained by the existence of DCs in different states of
maturation.4-6,9 However, it is now becoming clear
that some of these DC populations do not interconvert during in vitro
maturation and thus may derive from distinct hematologic precursors.
For example, human blood DCs exist in at least 2 distinct populations,
one expressing CD11c and the other interleukin-3 (IL-3) receptor In mouse, a small subset of DCs in spleen, thymus, and lymph nodes
express CD8 Murine splenic and lymph node DCs may also express
CD4.16,18,19,28 Together with CD8 Mice and media
Isolation of DCs
T-cell isolation, proliferation assays, and CTL killing of DCs Total T cells were prepared from spleen or lymph node by filtration through nylon wool. CD8+ T cells were prepared by immunomagnetic depletion using CD4 (GK1.5), CD19 (1D3), LY49G (4D11), and class II (2G9; anti-IA/IE) as described above for DC isolation. No difference was noted in T cells isolated from spleen or lymph node in terms of proliferation induced by the various DC subsets (data not shown). Allogeneic CTL lines were prepared according to Matzinger.33 Briefly, stimulator spleen cells from either Balb/c or C57Bl/6 mice were treated with mitomycin C (25 µg/mL; 30 minutes) or irradiated (25 Gy) and cultured for 5 days with allogeneic Balb/c or C57BL/6 spleen cells (2 × 106 stimulators with 4 × 106 responders in 2 mL complete IMDM per well in 24 well plates). For CTL proliferation assays allogeneic cultures were washed once in PBS and the blasts isolated by Lympholyte-M gradient (Cederlane; 1000g; 20 minutes, room temperature). Recovered blasts were immunomagetically depleted of CD19, Gr-1, LY49G, and CD4+ cells as described above. Purified CD8+ T-cell suspensions contained no detectable CD4+ T cells as assessed by flow cytometry. For allogeneic T-cell proliferation assays, graded doses of FACS-sorted DCs were added to 5 to 10 × 104 T cells as indicated in the figure legends. To monitor sensitivity of DCs to CTL killing, MACS-purified CD11c+ DCs were labeled with 5-chloromethylfluorescein diacetate (CMFDA; 2 µM; 10 minutes at 37°C; Molecular Probes, Eugene, OR) extensively washed and then 2 × 105 DCs incubated with various doses of allogeneic CTLs in 1 mL low-adhesion microtiter tubes (QSP, Biozym, Hess, Germany) with 5% GM-CSF csn, to minimize spontaneous DC apoptosis. After 4 hours, the cultures were pelleted and labeled with phycoerythrin (PE)-conjugated CD8 monoclonal antibody (mAb) for 30 minutes, washed, and resuspended in 200 µL PBS/2% FCS with 2 µg/mL
propidium iodide (PI). The same volume was acquired for each tube
during FACS acquisition using a constant time (30 seconds) acquisition,
as previously described.34 The absolute numbers of viable
DCs in the CTL/DC cultures from each subset were then determined by
gating CD8 /CMFDA+/PI or
CD8+/CMFDA+/PI events
during analysis.
In vivo priming for H-Y antigen cytotoxicity For determination of in vivo priming for cytotoxicity by DC subsets, 1 to 5 × 105 sorted C57/BL6 male DCs were injected into the lateral tail vein of female mice in 200 µL Hanks balanced salt solution (HBSS). After 14 to 20 days, spleens were removed and 4 × 106 female splenocytes restimulated with 2 × 106 male splenocytes in 2 mL I10 in 24-well plates. The "Just Another Method" (JAM) 3H-thymidine-based cytotoxicity assay was performed as described by Matzinger.33 Briefly, each well of restimulated splenocytes was resuspended in 0.4 mL I10 and the effectors diluted 3-fold in V-bottom plates (651 101; Greiner, Frickenhausen, Germany). Two day concanavalin A (Con A; 2 µg/mL) blasts from male or female splenocytes were labeled for the last 16 hours (at 2.5 × 106/mL) with 5 µCi (0.185 MBq)/mL 3H-thymidine, washed thrice in 2% FCS/PBS, and resuspended at 2 × 105/mL in I10. Each 100-µL well of effectors received 50 µL blasts. The plates were spun (2 minutes, 400g) and after 3.5 hours, DNA fragmentation in the targets was determined by liquid scintillation counting and percent cytotoxicity determined from the counts per minute as: (Spontaneous Experimental/Spontaneous)× 100.
Cell labeling and FACS The mAbs applied in this study are listed in Table 1. All incubation steps were 30 minutes on ice followed by a wash in cold 0.2% BSA/PBS. Low-density spleen cells were labeled with 50 µL N418 (hamster antimouse CD11c) csn and the appropriate rat mAb as indicated in Table 1. Washed cells were incubated with multiple species Ig-adsorbed fluorescein isothiocyanate (FITC)-antihamster Ig (Dianova) and PE-antirat Ig (Dianova). Cells were then washed and blocked in 25 µL 10% rat serum and Cy5-PE-conjugated CD4 (GK1.5), CD8 (53-6.7), or control IgG-conjugate added (Southern Biotechnology Associates, Eching, Germany). Cytoplasmic antigens were detected using the An der Grub kit (Dianova, Hamburg, Germany). For cell sorting, labeled low-density spleen cells were resuspended at 5 × 107 cells/mL in PBS plus 1 mM EDTA and sorted into CD11c+/CD4/CD8,
CD11c+/CD4+/CD8, and
CD11c+/CD4/CD8+ subsets using
a FACS Vantage cell sorter (Becton Dickinson, Heidelburg, Germany). SIINFEKL (single letter amino acid codes) peptide
bound to H-2Kb was detected on the surface of CD11c+
MACS-purified DCs as described in Figure 9 using the 25-D1.16 mAb35 (mouse IgG1).
Immunohistochemistry Serial frozen sections of mouse spleen samples were cut at 5 µm and placed onto slides coated with 3-amino-propyltriethoxy-silane (APES; Sigma, Deisenhofen, Germany), air-dried overnight, fixed in acetone for 10 minutes, rehydrated in Tris-buffered saline (TBS; 25 mM Tris/HCl, pH 7.4, 137 mM NaCl, 2.7 mM KCl), and blocked in a mixture of 5% BSA and 5% milk powder in TBS for 5 minutes. For double immunohistochemical staining of colocalized antigens, the sections were first incubated with the hamster mAb (N418; CD11c or control) at appropriate dilution followed by biotinylated-goat antihamster Ig antibody (107-066-142; Jackson Laboratories; 1/100) and then alkaline phosphatase (AP)-labeled streptavidin (E-2636; Sigma; 1/300) for 30 minutes each. Second, the sections were incubated with the rat-antimouse antigen-specific antibody, followed by incubation of the peroxidase-labeled rabbit antirat Ig antibody (P-0450; Dako; 1/100). Prior to substrate application, endogenous AP activity was blocked with 0.1% levamisole (Sigma) in TBS, pH 8.2. As substrates for the enzymes, first the AP-detecting APIII-Kit (blue, Vector, Burlingame, CA) and then the horseradish peroxidase (HRP)-specific 3-amino-9-ethyl carbazole (AEC; red, Dako; K3461) were applied. Sections were embedded in aqueous mounting media without prior counterstaining (Aquatex, Sigma).
Surface and cytoplasmic characterization of spleen DC subsets As shown recently by us and others,18,19 spleen DCs can be divided into 3 subsets, CD11c+/CD4/CD8 (~20%),
CD11c+/CD4+/CD8 (~60%), and
CD11c+/CD4/CD8+ (~20%) (Figure
1). Although distinct subsets of DCs
expressed the CD4 and CD8 T-cell markers, neither CD3 nor Thy 1.2 was
expressed (Figure 1 and Table 1). Overnight culture led to a series of changes in the phenotype of the various subsets, namely down-regulation of CD4 expression and up-regulation of costimulator molecules and
DEC-205. Analysis of class I ( 2m/) or class
II-deficient mice (which lack almost all CD8+ or
CD4+ T cells, respectively, due to defective thymic
positive selection) or RAG/ mice (which lack
all T and B cells) showed that the expression of CD4 or CD8 on DCs
was normal in these mutant mice and thus was not due to antigen pickup
from T cells (Figure 2). All subsets expressed the DEC-205 antigen, but DEC-205 staining was highest on the
CD8+ population. Nevertheless, DEC-205 levels were also
strongly increased on the CD8 subsets following
overnight culture (Figure 1 and Table 1). All subsets lacked the
macrophage markers MOMA-1, MOMA-2, and ERTR9. In contrast,
intracellular expression of FA-11, MIDC8, and 2A1 was noted on all
subsets. As shown in Table 1 and Figure 3, CD8+ DCs specifically
expressed the CD103 (the mouse homologue of the rat DC marker OX62) and
showed the highest levels of 5 and 6
integrins, CD24, CD44H molecules, sca-1, CD162 (PSGL-1), and CD62L.
Interestingly, expression of the Birbeck granule-associated Langerin
molecule36 was also confined to the CD8+
subset (Table 1). CD4+ DCs expressed the highest levels of
CD11b and LPAM-1 (47 integrin). F4/80
expression was detectable only on the CD8 subsets and
was highest on the CD4+ subset. The density of CD43 was
highest on the CD4/CD8 DC subset. No
differences in class I, class II, invariant chain, costimulator
molecule, heat shock protein expression, or in their culture-induced
up-regulation, was noted among the 3 subsets. To obtain information
about the morphology of the DC subsets, CD11c+ spleen cells
were sorted by FACS according to CD4 and CD8 expression as shown in
Figure 4. Most cells in each of the 3 subsets showed similar nondendritic round morphology and high
nuclear-to-cytoplasm volume ratio. The range of these features varied
similarly within each of the subsets (Figure 4). Occasional dendritic
morphology, consistent with the appearance of activated or mature DCs,
was noted with a small number of DCs in all 3 subsets. However, as shown in Figure 4, CD8+ DCs showed higher side scatter
compared to the smaller sized CD4/CD8 and
CD4+/CD8 subsets, suggesting a complex cell
surface, or more granular cytoplasmic content.
Anatomic localization of the CD4+ and CD8+ DC subsets Double-labeling analysis was performed using CD11c in conjunction with CD4 and CD8 to determine the location of the various DC subsets (Figure 5). A large number of CD11c+/CD4+ DCs were identified mainly in the marginal zone and T-cell areas, with a few examples in the red pulp (Figure 5B). The bright expression of CD8 on spleen DCs allowed the
detection of a clearly stained population that was more frequently
present in the red pulp, marginal zone, although a minority was present
in the T-cell areas (Figure 5C). CD4/CD8
DCs were noted in the marginal zones and red pulp, but also associated with or close to the T-cell areas (Figure 5D). No overlap of CD11c with
other T-cell or macrophage antigens (such as Thy-1.2 or MOMA-1 and
MOMA-2) was noted (Figure 5A and data not shown) demonstrating the
specificity of the CD4 and CD8 double-labeling.
In vitro migratory capacity of DC subsets in collagen lattices Two reports have demonstrated a reduced capacity of CD8+ DCs to home to the lymph nodes following
subcutaneous injection.22,27 One reason for this observed
defect might be a reduced migratory capacity of the CD8+
DCs. We therefore performed migration assays to test the motility of
the 3 DC subsets in 3-dimensional collagen lattices as
described.37 The DC subsets were isolated by FACS,
incubated in collagen lattices, and filmed, and their movement over a
period of 6 to 12 hours was tracked. In 3 experiments all DC subsets
showed comparable speeds (2-6 µm/min) of migration over the entire
time analyzed (data not shown).
Presentation of alloantigens and nominal peptide to naïve and cytotoxic T cells by DC subsets All 3 DC subsets demonstrated similar ability to stimulate unfractionated T cells in the 3-day mixed lymphocyte reaction (MLR) (Figure 6A). In contrast, CD8+ DCs were always very poor stimulators of resting or activated CD8+ T cells, even when the stimulator-to-responder ratio was increased up to 1:2 (Figure 6B,C). Interestingly, CD8 or CD8+ DCs appeared
to be similar in their ability to present alloantigens, because they
were both lysed with the same efficiency by allogeneic CTLs (Figure
7). Neither lipopolysaccharide nor CD40
treatment of CD8+ DCs overcame their inability to
effectively stimulate allogeneic CD8+ T-cell responses
(data not shown). Neither did the poor alloantigen presentation by
CD8+ DC appear to be due to the induction of anergy or
apoptosis in responding T cells, because mixing of FACS-purified
CD8+ DCs with the other CD8 DC subsets
did not result in reduced CD8+ T-cell proliferation. In
fact, addition of CD8+ DCs to either of the other
CD8 DC subsets led to a moderate increase in
CD8+ T-cell proliferation (data not shown). However, we
cannot rule out that signals from the CD8 subsets may
have enhanced the allostimulatory capacity of the CD8+
DCs. We next checked if the inability of the CD8+ DC
subset to stimulate CD8+ T cells was true for the
presentation of antigens other than alloantigens. For this purpose we
used transgenic F5 CD8+ T cells, which recognize the
influenza NP68 peptide in context of H-2Db. Surprisingly,
in several experiments CD8+ DCs were good stimulators of
resting CD8+ F5 T cells, especially at higher NP68 peptide
concentrations (Figure 8A). However, in
experiments where the DC/T-cell ratio was low, a result more similar to
the allogeneic system was observed, with only low levels of T-cell
proliferation induced by the CD8+ DCs (Figure 8B). Thus,
only under certain optimal stimulation conditions do
CD8+ DCs appear capable of stimulating effective in
vitro CD8+ T-cell responses.
Turnover of class I-peptide complexes on CD8 + DC subset was poor at stimulating
class I-restricted T cells and this could not be explained by lack of
class I or costimulator molecule expression, we reasoned this
differences might be due to a differential turnover of class I-peptide
complexes between the DC subsets. This might result in a faster loss of antigenic-peptide from the class I molecules on the CD8+
DC subset. To answer this question, we used the 25-D1.16 mAb, which
recognizes SIINFEKL peptide in the context of
H-2Kb.35 DCs were purified using CD11c-coated
MACS beads and incubated with varying concentrations of SIINFEKL for 4 hours and then thoroughly washed free of uncomplexed peptide. The DCs
were then chased by culture in the absence of SIINFEKL and the relative
amount of class I-bound SIINFEKL determined by 25-D1.16 staining after
0, 24, and 48 hours. Such an analysis reflects the amount of peptide lost from class I complexes through class I-peptide complex shedding or endocytosis, as well as peptide loss from the class I at the cell
surface. As shown in Figure 9, no major
differences between the class I-peptide stability was observed between
the CD8+ and the CD8 DC subsets. In
fact in all 3 experiments, the stability of class I-peptide complexes
on the surface of the CD8+ DC subset was slightly higher
compared to CD8 DCs.
In vivo priming of cytotoxic responses by the DC subsets We next wished to test the ability of the various DC subsets for in vivo CTL priming. Because peptide-pulsing protocols lead to DCs that express extremely high levels of class I-peptide complexes, we reasoned this might lead to inadvertent loading of endogenous antigen-presenting cells (APCs) after injection of pulsed DCs, as has been suggested to occur in certain systems.27 Instead we chose a weakly expressed antigen expression system that might reflect physiologic levels of cytoplasmic antigen expression and that would therefore be unlikely to transfer significant quantities of class I-associated peptide to endogenous host APCs. The H-Y antigens are encoded by the Y chromosome and are ubiquitously expressed by all cell types studied so far, including DCs and as few as 10 copies of the several H-Y peptides may be expressed per cell.38 For our purposes, female C57BL/6 mice were immunized intravenously with 1 to 5 × 105 FACS-sorted syngeneic male DCs of the 3 DC subtypes. As shown in Figure 10, both CD8+ DCs and CD4/CD8 DCs
were consistently able to induce potent anti-H-Y cytotoxic responses
in female mice. Interestingly, CD4+ DCs were always
several-fold weaker at priming CTL responses as compared to the other
CD4 DC subsets and CD4+ DCs failed to prime
detectable H-Y CTLs in 1 of 3 experiments. In vitro experiments
confirmed that splenocytes of mice primed by all 3 DC subsets (but not
from HBSS-primed mice) contained similar levels of H-Y-specific
CD4+ and CD8+ T cells that had expanded on
contact with male splenocytes. Thus, a lower level of H-Y presentation
is unlikely to be the reason for the weaker CTL expansion by the
CD4+ DC subset (data not shown).
Initial work on the function of the CD8 Given the weak stimulation of CD8+ T cells in vitro by
CD8 Recent work demonstrates the heterogeneity of mouse DCs. From our
analysis of the expression of surface and cytoplasmic molecules, we
further emphasize the complexity of these DC subsets with the identification of several hitherto unidentified differences between the
DC subsets, as well as the confirmation of other described differences.
As determined here and in other laboratories (K. Inaba, C. Reis e
Sousa, personal communication), CD8 To date, the function of the high-level expression of CD8 Through use of a sensitive double-labeling technique we have provided
the first description of the anatomic distribution of the 3 CD11c+ DC subsets in normal spleen (Figure 5).
Interestingly, although CD8 From population turnover studies of Shortman et
al,29 the 3 DC subsets incorporated
bromodeoxyuridine (BrdU) label at similar rates and thus do not appear
to derive from one another. This study leaves open the question of
whether these precursors are very early hematopoietic progenitors, or
alternatively, a late DC precursor with a high turnover rate that seeds
the spleen. For the latter model, the subsequent DC phenotype (eg, CD4
or CD8 expression) might be determined in a stochastic manner by environmental signals. The fast BrdU incorporation into DCs suggests that the precursors are rapidly dividing, although under the correct signals resident spleen DCs may also be capable of cell
division.46,47 Earlier adoptive transfer experiments
suggested the existence of a very early, common precursor cell for T
cells and CD8 This study adds weight to the thesis that DCs are present as
specialized subsets with distinct surface phenotype and different abilities to induce T-cell proliferation and T cell-mediated
cytotoxicity. In particular, CD8
The authors would like to thank Sonja Rotzoll for excellent technical assistance with cell sorting; Drs Sem Saeland, Ron Germain, Patrizia Stoitzner, Bjørn Henriksen, Susan Schellworth-Sherz, Thomas Hunig, Wolfgang Fischer, Manfred Lutz, Polly Matzinger, Ashraf Ab delhafez, Peter Friedl, Cathy Toben, Georg Kraal, and Ralph Steinman for assistance with antibodies, peptides, cell lines, and advice with the cytotoxicity assays. We gratefully acknowledge the reviewers' suggestions and contribution to the manuscript. The continuing support of Prof J Dietl and Dr J. C. Becker is gratefully acknowledged.
Submitted May 31, 2001; accepted October 22, 2001.
Supported by grants from the German Ministry for Education and Research (BMBF01KX9820/L, IZKF-01KS9603, and SFB 465).
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: Alexander D. McLellan, Department of Dermatology, University of Würzburg, Joseph-Schneider Str 2, Würzburg 97080, Germany; e-mail: alex.mclellan{at}mail.uni-wuerzburg.de.
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  D. Piccioli, C. Sammicheli, S. Tavarini, S. Nuti, E. Frigimelica, A. G.O. Manetti, A. Nuccitelli, S. Aprea, S. Valentini, E. Borgogni, et al. Human plasmacytoid dendritic cells are unresponsive to bacterial stimulation and require a novel type of cooperation with myeloid dendritic cells for maturation Blood, April 30, 2009; 113(18): 4232 - 4239. [Abstract] [Full Text] [PDF]
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D. M. Reid, M. Montoya, P. R. Taylor, P. Borrow, S. Gordon, G. D. Brown, and S. Y. C. Wong Expression of the {beta}-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions J. Leukoc. Biol., July 1, 2004; 76(1): 86 - 94. [Abstract] [Full Text] [PDF]
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F.-X. Hubert, C. Voisine, C. Louvet, M. Heslan, and R. Josien Rat Plasmacytoid Dendritic Cells Are an Abundant Subset of MHC Class II+ CD4+CD11b-OX62- and Type I IFN-Producing Cells That Exhibit Selective Expression of Toll-Like Receptors 7 and 9 and Strong Responsiveness to CpG J. Immunol., June 15, 2004; 172(12): 7485 - 7494. [Abstract] [Full Text] [PDF]
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B. G. Dorner, H. R.C. Smith, A. R. French, S. Kim, J. Poursine-Laurent, D. L. Beckman, J. T. Pingel, R. A. Kroczek, and W. M. Yokoyama Coordinate Expression of Cytokines and Chemokines by NK Cells during Murine Cytomegalovirus Infection J. Immunol., March 1, 2004; 172(5): 3119 - 3131. [Abstract] [Full Text] [PDF]
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M. Leverkus, A. D. McLellan, M. Heldmann, A. O. Eggert, E.-B. Brocker, N. Koch, and E. Kampgen MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways Int. Immunol., August 1, 2003; 15(8): 993 - 1006. [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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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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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]
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Top
Abstract
Introduction
is still
controversial since Ohteki et al showed that IFN-
T cells.