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*
Laboratory of Plasma Derivatives, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892;
Immunobiology Laboratory, Imperial Cancer Research Fund, London, United Kingdom;
Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga, Japan; and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-secreting T cells, which are usually required for effective
immunity to bacterial and viral pathogens (1, 2). The
heterodimeric cytokine, IL-12, is critical for Th1 development
(3, 4, 5). Nonetheless, the identity of IL-12-producing cells
and the regulation of IL-12 production in vivo after infection remain
largely unknown. Recent studies have shown that dendritic cells
(DC)2 may be effective
Th1-promoting APC, in part because of their ability to produce IL-12
when stimulated by pathogens, independently of IFN- priming
(6, 7, 8, 9, 10, 11). Murine DC subsets have been described, which are
distinguished by the presence or absence of CD8
expression and some
studies have suggested that CD8+ DC promote Th1
responses, whereas CD8- DC promote Th2 responses
(12, 13). Similarly, studies in the human have indicated
the existence of ontogenically distinct DC populations that can
differentially prime Th responses (14). These observations
have led to the notion that DC subsets function to promote different,
even polarized, immune responses. However, other data suggest that DC
subsets are not preprogrammed to induce different Th
responses but are modulated by environmental signals to do so
(15, 16).
The adjuvant and carrier heat-killed Brucella abortus (HKBA)
is a well-established Th1-promoting stimulus (17, 18).
HKBA alone, or conjugated to Ags, induces IFN-, IL-12, and IL-10 and
promotes formation of long-lived Th1 responses, CTL, and
complement-fixing Abs (18, 19, 20, 21, 22, 23). HKBA-mediated Th1
responses, including induction of Th1-associated Abs, are IL-12
dependent (22). Although live B. abortus
organisms are primarily taken up by macrophages, the identity of
IL-12-secreting cells after HKBA injection has not been elucidated, nor
is it known whether APC other than macrophages are capable of ingesting
HKBA. In addition, the site of IL-12 secretion in relation to areas
occupied by T cells has not been characterized following HKBA
injection.
In the present study, we characterized the early events following mouse i.v. challenge with HKBA, focusing on IL-12 responses. Flow cytometric analysis showed that the majority of injected HKBA was taken up by macrophages and granulocytes, although IL-12 production was limited to DC. HKBA also induced DC migration to the T cell areas of splenic white pulp (WP) within 6 h of i.v. injection, leading to colocalization of HKBA, DC, and IL-12 in the T cell areas of the WP. A prominent IL-12-producing, CD8- DC subset was observed after HKBA immunization. In contrast, injection with a different Th1-promoting microbial preparation, soluble tachyzoite Ag (STAg) from Toxoplasma gondii, resulted in IL-12 production mainly by CD8+ DC. In IL-10 knockout (KO) mice, greater proportions of both CD8+ and CD8- DC produced IL-12 after HKBA, indicating that both subsets are susceptible to regulation by this anti-inflammatory cytokine. These findings characterize the anatomical and phenotypic correlates of the Th1 response to HKBA, suggest that CD8- DC can be associated with generation of Th1 responses, and also demonstrate that different proportions of DC subsets can be triggered to produce IL-12, depending upon the type of microbial challenge. These results favor a model wherein either CD8+ or CD8- DC may promote a Th1 response, depending upon the type of microbial stimulation encountered.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female BALB/c mice were obtained from the Division of Cancer Treatment, National Cancer Institute (Frederick, MD). Female IL-10-deficient mice (KO) on a C57BL/6 background, C57BL/6 mice, and IL-12 p40 KO mice on a BALB/c background were obtained from The Jackson Laboratory (Bar Harbor, ME). Mice were used at 6–12 wk of age. Mice were housed in specific pathogen-free rooms and were used according to National Institutes of Health standards for animal use and care, under a protocol approved by the Center for Biologics Evaluation and Research Animal Care and Use Committee.
Microbial stimuli
Heat killed B. abortus was kindly provided by Dr. B. Martin at the U.S. Department of Agriculture (Ames, IA) and was washed extensively with PBS before use. Soluble T. gondii tachyzoite Ag (STAg) was a kind gift from the laboratory of A. Sher (National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD), and was prepared as previously described (24). HKBA was injected at a dose of 108 organisms/mouse i.v. The dose of STAg used was 25 µg/mouse i.v.
Immunohistochemistry
Spleens were frozen in Tissue-Tek OCT compound (Sakura Finetek
USA, Torrance, CA). Frozen sections were processed as previously
described (6) with the following modifications:
8-µm frozen sections were cut and fixed with 4% paraformaldehyde
rather than acetone (7). Sections were stained with Abs
against the following: IL-12 p40 (C15.6 or C17.8), CD11c (HL3), TCR
(H57-597), B220 (RA3-6B2), and isotype controls (all from BD
PharMingen, San Diego, CA). In initial experiments, for staining of
HKBA, HRP-mBA Ab, kindly supplied by Dr. Klaus Nielson, was used.
Subsequent experiments shown here yielded similar staining and were
done using goat polyclonal anti-B. abortus Ab (Lampire
Biological Laboratories, Pipersville, PA). Staining specificity was
assured by adsorbing the antiserum with HKBA, which abrogated staining
of spleen sections from mice injected with HKBA. Normal goat serum,
used as an isotype control, also did not stain mouse spleen sections.
Anti-B. abortus Ab was followed by biotin-conjugated donkey
anti-goat F(ab')2 (Jackson Immunoresearch,
West Grove, PA), then HRP conjugated to streptavidin (Jackson
Immunoresearch).
After staining, sections were washed in distilled water, dried, and mounted in Permount (Fisher Scientific, Fairlawn, NJ). Sections were photographed on a Zeiss Axiophot microscope (Zeiss, Thornwood, NY) using Kodachrome 25 film (Eastman Kodak, Rochester, NY). Slides were scanned using a Nikon LS-200 scanner (Melville, NY) and Adobe Photoshop software (Adobe Systems, San Jose, CA).
Flow cytometry
Spleen cell suspensions were prepared by collagenase digestion,
and in some cases low-density spleen cells were subsequently enriched
using a 35% BSA gradient as previously described (25).
All buffers used during collagenase digestion and cell preparation for
staining contained 3 µM monensin (Sigma, St. Louis, MO). The
remaining procedure was performed as described elsewhere (6, 26), with a few modifications. Briefly, cells were fixed with
2–4% paraformaldehyde in PBS/EDTA at 37°C for 10 min, washed, and
kept in PBS/EDTA/1% FCS overnight or were frozen in 10% DMSO/90% FCS
at -72°C until analysis. For intracellular cytokine staining, cells
were washed and stained in PBS/EDTA/1% FCS buffer containing 0.1%
saponin. Anti-IL-12 p40 staining and staining with surface markers was
usually done simultaneously, after determining that saponin treatment
did not affect the expression of the surface markers being analyzed.
The following Abs were used: PE- or FITC- or CyChrome-conjugated
anti-IL-12p40 (C15.6), DC marker CD11c (HL3), macrophage marker
Mac-1 (M1/70), B cell marker B220 (RA3-6B2), CD8
(7), granulocyte marker Ly-6G (Gr-1 Ag, clone
RB6-8C5), and isotype-matched controls (all obtained from BD
PharMingen). Goat anti-B. abortus serum (Lampire
Biological Laboratories) was used for staining HKBA-associated cells,
followed by biotin-conjugated donkey anti-goat
F(ab')2 conjugated to FITC, R-PE, or CyChrome (BD
PharMingen).
Two hundred thousand to 400,000 events were collected on a FACScan cytometer and analyzed using CellQuest software (BD Biosciences, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Microbial products, such as LPS and STAg, can elicit IL-12
secretion and DC migration to the T cell areas of splenic WP (6, 27). Since HKBA induces IL-12-dependent, long-lived Ag-specific
T cell responses when used as an adjuvant or carrier, we undertook to
see whether it could be found in WP and whether the HKBA presence
coincided anatomically and chronologically with IL-12 secretion and DC
localization. Examination of spleen sections demonstrated that HKBA was
detected mainly in spleen red pulp (RP) within 3 h of i.v.
injection (Fig. 1
A). By 8
h, HKBA was detected in the WP as well as RP and remained in both of
these locations for at least 3 mo (Fig. 1A and data not
shown). The delayed appearance of HKBA in the WP suggests transport to
this area by cells. Similarly, DC migration to the WP began within
3 h of HKBA injection (Fig. 1B). By 8 h, DC were
almost exclusively localized in distinct areas of spleen WP. This
pattern was only transiently maintained; by 24 h, DC were once
again mostly absent from the WP and were scattered in RP and marginal
zones (MZ). IL-12 expression within the first 8 h was similar to
DC distribution (Fig. 1C). At 3 h, most IL-12 p40
expression was seen in the RP and MZ. By 8 h, IL-12 expression was
limited to distinct areas of the WP, which coincided with the areas
where DC were located (Fig. 1, B and C).
Twenty-four hours after injection, IL-12 expression was down-regulated,
although, interestingly, HKBA could still be easily detected in the WP.
The persistence of HKBA Ags in the WP therefore did not enable
continued IL-12 secretion.
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). By 6 h, DC had migrated and
could be seen to reside in the T cell zone of the WP, which coincided
with the area in which IL-12 secretion was detected. Interestingly,
IL-12 secretion was distributed in large, discrete patches, whereas DC
were more abundant in the same location, suggesting that many more DC
are present in the WP than are producing IL-12. Although HKBA is
predominantly seen in the T cell area, study of many serial sections
revealed that sparse HKBA staining could also be detected in B cell
areas. Hapten linked to HKBA was also transported into the
periarteriolar lymphoid sheath and colocalized with IL-12
staining (data not shown).
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Candidate IL-12-producing cells in HKBA-treated mice include DC,
macrophages, granulocytes, and B cells. IL-12 expression was detected
by flow cytometry 3 h after HKBA injection in splenic DC
(CD11c+, Mac-1low), but not
macrophages (Mac-1high) (Fig. 3). Staining from this experiment and
other experiments indicated that CD11c+
populations are typically Mac-1low (data not
shown) as noted by others (28, 29, 30). Some fluorescence was
observed in the
CD11c-IL-12+ quadrant.
Similar levels of fluorescence were observed in isotype controls and in
PBS-treated spleens of IL-12 KO mice (data not shown). We believe that
this reflects autofluorescence and/or background staining, as observed
by others (31). HKBA-induced IL-12 expression was not
observed in B cells or granulocytes (data not shown). IL-12 was clearly
detected in both CD8+ and
CD8- subsets of DC, in contrast to STAg, which
stimulated primarily the CD8+ subset (Fig. 4). These results demonstrate that
different profiles of DC subset stimulation occur when distinct
Th1-inducing microbial preparations are used.
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80% of
detectable HKBA was consumed by phagocytic cell populations which did
not produce IL-12. These results show that HKBA uptake by cells per se
does not induce IL-12, an activity which appears to be limited to
DC. Experiments were also performed to determine whether HKBA-associated DC exclusively produce IL-12 after injection. At 3 h, the majority of DC (73–83%, n = 4 BALB/c mice) did not stain for HKBA and did not express IL-12. Of the remaining DC, 2–8% were HKBA associated and IL-12+. Two to 12% were associated with HKBA staining, but did not express IL-12. Finally, 7–17% were not associated with HKBA yet still expressed IL-12. In the case of the latter population, it is possible that HKBA stimulates DC to produce IL-12 without being attached or internalized, or that it is internalized but because of processing, or Ab insensitivity for minute amounts of HKBA contained in cells, it is not detected in the IL-12-producing cells.
IL-10 controls the intensity and duration of IL-12 expression
IL-10 suppresses IL-12 production in vitro, and in vivo studies
have shown that IL-10 is a critical cytokine which protects the host
from inflammation-mediated damage (34, 35, 36, 37, 38, 39, 40, 41). Previous
studies show that HKBA induces IL-10 mRNA in vivo and IL-10 protein in
vitro (19, 42). To determine whether IL-10 is responsible
for the rapid down-regulation of DC-produced IL-12 after HKBA, IL-10 KO
mice were injected with HKBA and compared with control C57BL/6 mice
(Fig. 5). The intensity of IL-12 staining
in IL-10 KO mice at 3 h was greater than that seen in the control
C57BL/6 strain. By 8 h, IL-12 staining was limited to WP in normal
mice, but IL-10 KO mice had abundant IL-12 staining cells remaining in
the RP as well as in the WP. This pattern was never detected beyond
3 h in C57BL/6 or BALB/c mice. In contrast to normal mice, IL-12
persisted in the WP and RP of IL-10 KO mice 24 h after HKBA
injection. By 48 h, scant IL-12 could still be detected in the WP
(data not shown). Therefore, in the absence of IL-10, IL-12 expression
was intensified and prolonged. Eventually IL-12 expression was
down-regulated in an IL-10-independent fashion in IL-10 KO mice. The
apoptosis of DC which has been described after LPS injection could
account for eventual abrogation of IL-12 expression (27),
although we have not observed a large-scale decrease of spleen DC at
24–48 h postinjection with HKBA.
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). However, IL-10 KO
mice had greater numbers of IL-12-secreting
CD11c+ cells compared with control C57BL/6 mice.
Strikingly, a substantial increase in the number of
CD11clow IL-12-secreting cells was seen at 6
h from the spleens of IL-10 KO, but not normal mice. Additional
analysis showed that this IL-12-secreting
CD11clow population was not comprised of
granulocytes or macrophages (Fig. 6). CD8+ and
CD8- DC subsets were also examined to determine
whether preferential enhancement of IL-12 secretion occurred in one of
these populations. A greater proportion of IL-12-expressing cells was
seen in both populations, more so in the CD8-
population, indicating that CD8+ and
CD8- DC are both regulated by IL-10 after HKBA
(Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because IL-12 is critical for the Th1 response to HKBA, as it is in
many other systems, we undertook a detailed examination of
IL-12-secreting cells. Three hours after HKBA injection, IL-12 was
detected mainly in the RP and MZ, and by FACS, all of the
IL-12-secreting cells were CD11c+ and
Mac-1low. Although DC exclusively produced IL-12
after HKBA, they only accounted for 10% of HKBA uptake by spleen
cells. The majority of cells associated with HKBA were granulocytes and
macrophages, which normally function as scavenger cells in the RP
(45). Whether or not these cells are otherwise inert after
HKBA injection is under study; they may produce other cytokines, such
as TNF-, IL-1, and IL-10, that enhance or suppress the IL-12
response to HKBA. Mouse spleens contain HKBA for at least 3 mo after
injection; by 5 mo after injection HKBA can no longer be
immunohistochemically detected. Although most HKBA at 3 mo is detected
in RP, some also remains in the WP (data not shown). It is tempting to
speculate that the persistence of HKBA in spleens contributes to the
long-term T cell memory responses that are observed after mice receive
HKBA attached to proteins or peptides (20, 22).
Previous functional studies have shown that DC in mice can be divided into CD8+ and CD8- subsets, and that in the systems observed, CD8+ DC in mice secreted higher levels of IL-12 and were better Th1 inducers (6, 29). In contrast, CD8- DC, after Ag-pulsing in vitro, have been shown to induce Th2 responses in vivo (12, 13). It was expected that HKBA, given its strong Th1-inducing and Th2-suppressing properties, would preferentially stimulate IL-12 secretion from CD8+ DC. Surprisingly, CD8- DC comprised approximately two-thirds of the early IL-12-secreting population. The production of IL-12 by sizeable proportions of both DC subsets after HKBA injection, challenges the notion of preferential Th1 or Th2 induction by one of the DC subsets and suggests that the context of activation, and the activating substance, rather than the DC subset per se are the most critical factors that orchestrate the resulting type of immune response (15). This view is supported by the different abilities of STAg and HKBA to stimulate IL-12 secretion from CD8+ and CD8- DC populations. Differences among pathogen extracts in their ability to stimulate DC subsets are likely to depend upon a complex combination of pattern recognition receptors which differ among DC and conserved components which differ among the stimulating microbial preparations (8, 46).
Because HKBA induces IL-10, it was of interest to determine whether DC subsets were differentially influenced by IL-10 and whether the presence of IL-10 inhibited IL-12 secretion from other populations of cells. As in normal mice, CD11c+ cells accounted for the majority of IL-12 expression in IL-10 KO mice. An increase of IL-12-secreting CD8+ and CD8- DC occurred in IL-10 KO mice compared with normal mice, indicating that both subsets are regulated by IL-10. However, a CD11clow population of cells in IL-10 KO mice was newly enabled to express IL-12 6 h after injection. Although macrophages may express low levels of CD11c, Mac-1high cells were not responsible for this IL-12. The IL-12-expressing, CD11clow cells in IL-10 KO mice could be immature DC, as has been suggested previously (29). This CD11clow population in IL-10 KO mice correlates with the unusual presence of IL-12 in the RP at 6–8 h by immunohistochemistry, further suggesting that in the absence of IL-10, an additional DC population is allowed to express this cytokine. Alternatively, these could be DC which have down-regulated CD11c after stimulation. Future experiments are planned to further characterize the CD11clow population and the very small CD11cneg population which secretes IL-12.
The rapidity of IL-12 enhancement in IL-10 KO mice, within 3 h after injection, suggests that IL-10 secretion is important at early time points. The up-regulation of IL-12 in IL-10 KO mice could be explained by lack of constitutive or lack of HKBA-induced IL-10. We favor the likelihood that HKBA induces IL-10, since we have observed this ability in vitro, and we and others have observed induction of IL-10 mRNA in mouse spleens within 1 h of HKBA injection (19, 42).
IL-12 secretion after HKBA is short-lived. Since IL-10 clearly controls the level of IL-12 secretion, it could also be responsible for the down-regulation of IL-12 to baseline levels. This idea is supported by previous experiments which show that IL-10 mRNA continues to be expressed for at least 6 days after HKBA injection (19). However IL-12 down-regulation in IL-10 KO mice was delayed, but did occur between 24 and 48 h after injection. Thus, other mechanisms in addition to IL-10 must play a role in IL-12 down-regulation after HKBA, as described for STAg (26). Studies with LPS have shown that DC in the WP undergo apoptosis between 24 and 48 h after injection, which would account for loss of cytokine secretion (47). However, although the DC in WP mostly disappear by 24 h after HKBA, the widespread splenic DC depletion seen after LPS does not occur. Another possibility is that, similar to STAg, HKBA stimulation results in eventual down-regulation of IL-12 which is accompanied by refractoriness of DC to further stimulation. This recently described "immune paralysis" is not IL-10 mediated (26).
HKBA has been established as a model for the induction of Th1 responses and suppression of Th2 responses. The results of the present study demonstrate that HKBA causes colocalization of Ag, IL-12, and professional APC in T cell areas of lymphoid tissue. The IL-12 response was rapidly down-regulated in a partially IL-10-dependent fashion. Thus, HKBA as a carrier naturally targets Ag to DC in a location which favors development of tightly controlled Th1 immune responses. The HKBA model will be useful in the future for understanding the relationship between CD8+ and CD8- DC and the fate of DC after they have delivered cytokines, Ag, and costimulation to T cells. Our experiments support a model of DC subset activation where either subset may be involved in a Th1 response and the stimulation of IL-12 secretion by a subset depends upon the particular antigenic stimulus, rather than upon an innate predisposition toward Th1 promotion. Understanding the characteristics of microbial preparations which stimulate DC subsets, and the DC subsets themselves, should enhance development of more effective Th1-inducing adjuvants for prevention and treatment of viruses and allergic conditions.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cell; HKBA, heat-killed Brucella abortus; WP, white pulp; STAg, soluble T. gondii tachyzoite Ag; KO, knockout; RP, red pulp; MZ, marginal zone.
Received for publication August 23, 2000. Accepted for publication May 30, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ and CD8-- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J. Exp. Med. 189:587. regulates the isotypes of Ig secreted during in vivo humoral immune responses. J. Immunol. 140:1022.[Abstract]
in CD4+ T cells. Int. Immunol. 5:877.. AIDS Res. Hum. Retroviruses 8:479.[Medline]
production. Eur. J. Immunol. 23:2223.[Medline]
). Curr. Opin. Immunol. 9:17.[Medline]
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I. L. Dodge, M. W. Carr, M. Cernadas, and M. B. Brenner IL-6 Production by Pulmonary Dendritic Cells Impedes Th1 Immune Responses J. Immunol., May 1, 2003; 170(9): 4457 - 4464. [Abstract] [Full Text] [PDF]
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 J. Aliberti, O. Schulz, D. J. Pennington, H. Tsujimura, C. R. e Sousa, K. Ozato, and A. Sher Essential role for ICSBP in the in vivo development of murine CD8alpha + dendritic cells Blood, January 1, 2003; 101(1): 305 - 310. [Abstract] [Full Text] [PDF]
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J. M.M. den Haan and M. J. Bevan Constitutive versus Activation-dependent Cross-Presentation of Immune Complexes by CD8+ and CD8- Dendritic Cells In Vivo J. Exp. Med., September 16, 2002; 196(6): 817 - 827. [Abstract] [Full Text] [PDF]
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G. Miller, V. G. Pillarisetty, A. B. Shah, S. Lahrs, Z. Xing, and R. P. DeMatteo Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Overexpression In Vivo Results in the Long-Term Recruitment of a Distinct Dendritic Cell Population with Enhanced Immunostimulatory Function J. Immunol., September 15, 2002; 169(6): 2875 - 2885. [Abstract] [Full Text] [PDF]
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F. Fallarino, U. Grohmann, C. Vacca, R. Bianchi, M. C. Fioretti, and P. Puccetti CD40 Ligand and CTLA-4 Are Reciprocally Regulated in the Th1 Cell Proliferative Response Sustained by CD8+ Dendritic Cells J. Immunol., August 1, 2002; 169(3): 1182 - 1188. [Abstract] [Full Text] [PDF]
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M. Dalod, T. P. Salazar-Mather, L. Malmgaard, C. Lewis, C. Asselin-Paturel, F. Briere, G. Trinchieri, and C. A. Biron Interferon {alpha}/{beta} and Interleukin 12 Responses to Viral Infections: Pathways Regulating Dendritic Cell Cytokine Expression In Vivo J. Exp. Med., February 19, 2002; 195(4): 517 - 528. [Abstract] [Full Text] [PDF]
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P. J. O'Connell, W. Li, Z. Wang, S. M. Specht, A. J. Logar, and A. W. Thomson Immature and Mature CD8{alpha}+ Dendritic Cells Prolong the Survival of Vascularized Heart Allografts J. Immunol., January 1, 2002; 168(1): 143 - 154. [Abstract] [Full Text] [PDF]
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