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Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. In contrast, a synthetic dsRNA, polyinosinic
polycytidylic-acid, induced CD11c+ DC, but not pre-DC2 or
monocytes, to produce IFN-
. These data indicate that CpG DNA and
polyinosinic-polycytidylic acid stimulate different types of cells to
produce type I IFN and that it is important to select
oligodeoxynucleotides containing particular CpG motifs to induce
pre-DC2 to produce type I IFN, which may play a key role in the strong
adjuvant effects of CpG DNA. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two classes of nucleic acids, namely 1) bacterial CpG DNA that contains immunostimulatory unmethylated CpG dinucleotides within specific flanking bases (referred to as CpG motifs) (4) and 2) dsRNA synthesized by various types of viruses (5), represent important members of the microbial components that enhance immune responses. Recent studies have shown that oligodeoxynucleotides (ODNs) containing CpG motifs (6, 7) and synthetic dsRNA, e.g., polyinosinic-polycytidylic acid (poly(I:C)) (8, 9), are capable of inducing DC to produce proinflammatory cytokines and to express high levels of costimulatory molecules.
A series of studies by Tokunaga and Yamamoto et al. has shown that
bacterial DNA or synthetic ODNs containing unique palindromic CpG
motifs induce human PBMC (10) and mouse spleen cells
(11) to produce type I IFN (IFN-) (reviewed in Ref.
12). Poly(I:C) was originally synthesized as a potent
inducer of type I IFN (13, 14). Type I IFN plays an
essential role in antiviral innate immunity and is widely used to treat
viral hepatitis and various types of cancers (15). These
effects appear to be due to direct inhibition of viral replication in
infected cells and to the pleiotropic immunomodulating activity of type
I IFN (15), such as 1) enhancing the cytotoxicity of NK
cells and macrophages (15), 2) inducing T cell activation
(16), 3) maintaining the survival of activated T cells
(17), 4) stimulating human CD4+ T
cells to produce a Th1 cytokine IFN-
(18), and 5)
inducing the expression of TNF-related apoptosis-inducing ligand on T
cells and thereby enhancing T cell cytotoxicity (19).
Thus, CpG DNA and poly(I:C) are believed to be promising adjuvants for
vaccination against infections and cancers due to their DC-stimulating
and type I IFN-inducing capacity.
To understand the mechanisms underlying the induction of type I
IFN by CpG DNA and poly(I:C) and to increase their efficacy as
immunological adjuvants, it is important to determine which cells
produce type I IFN in response to CpG DNA and poly(I:C). Two groups
have recently shown that the main producers of type I IFN in human
blood, designated natural IFN--producing cells (IPC), are
identical with
CD4+IL-3RhighCD3-CD11c-
type 2 dendritic cell precursors (pre-DC2) (20, 21), which
differentiate into DC in response to IL-3 (22) or viruses
(23). Pre-DC2 IPC produce 1000 times more type I IFN than
do CD11c+ blood immature DC, monocytes, and
monocyte-derived DC in response to viral stimulation (20).
In this study we asked whether pre-DC2 will produce type I IFN in
response to CpG DNA and poly(I:C). We show that 1) pre-DC2, but not
CD11c+ DC or monocytes, produce type I IFN in
response to CpG ODNs containing particular palindromic sequences,
and that 2) CD11c+ DC, but not pre-DC2 or
monocytes, produce type I IFN in response to poly(I:C).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following ODNs were purchased from Research Genetics (Huntsville, AL): 1668, TCCATGACGTTCCTGATGCT (6); 2117, T*CGT*CGTTTTGT*CGTTTTGT*CGTT (*C, methylated cytosine) (24); 2006, TCGTCGTTTTGTCGTTTTGTCGT (24); ACC-30, ACCGATACCGGTGCCGGTGACGGCACCACG (10); AAC-30, ACCGATAACGTTGCCGGTGACGGCACCACG (10); and GAC-30, ACCGATGACGTCGCCGGTGACGGCACCACG (10) (underlines indicate palindromic sequences). ODNs 1668, 2117, and 2006 are phosphorothioate forms, and ACC-30, AAC-30, and GAC-30 are phosphodiester forms. The phosphorothioate ODNs were added at 0 h at 0.1 µM (0.6 µg/ml) or 1 µM (6 µg/ml), and the phosphodiester ODNs were added at 0, 4, and 16 h, 5 µM (46 µg/ml) at each time point, to compensate for their degradation by DNase activity in medium.
Isolation and culture of cells
Monocytes, CD11c+ DC, and pre-DC2 were isolated from human peripheral blood as previously described (22, 23). The cells were cultured for 24 h in RPMI 1640 containing 10% FCS at 2 x 104/200 µl in round-bottom 96-well culture plates in the presence of ODNs or 50 µg/ml poly(I:C) (Sigma, St. Louis, MO). Adult dermal fibroblasts (Clonetics, Walkersville, MD) were maintained as recommended by the company and were stimulated with 50 µg/ml poly(I:C) for 24 h at 7.5 x 104/ml in 12-well culture plates.
Analysis of viability of pre-DC2 stimulated with ODNs or poly(I:C)
Pre-DC2 cultured for 24 h without stimulation or with ODNs or poly(I:C) were stained with propidium iodide and analyzed with a FACScan flow cytometer (Becton Dickinson, San Jose, CA). After cell debris was excluded by an appropriate forward scatter threshold, the percentages of propidium iodide-negative cells were calculated.
Flow cytometric analysis of the expression of CD80 and CD86
Freshly isolated pre-DC2 and pre-DC2 stimulated with ODNs for 24 h were stained with PE-conjugated anti-CD80 (L307.4; Becton Dickinson), PE-conjugated anti-CD86 (2331; PharMingen, San Diego, CA), or an isotype control Ab. CD11c+ DC cultured for 24 h without stimulation or with poly(I:C) were stained with FITC-conjugated anti-CD80 (L307.4), FITC-conjugated anti-CD86 (2331), or an isotype control Ab. The cells were analyzed with a FACScan flow cytometer. Dead cells were excluded by staining with propidium iodide.
Quantitation of cytokines by ELISA
An IFN- ELISA kit, an IL-12 ELISA kit (BioSource
International, Camarillo, CA), and an IFN- ELISA kit (FUJIREBIO,
Tokyo, Japan) were used to analyze cytokine production.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Without any stimuli, the majority of pre-DC2 rapidly die within
24 h (22, 23) (Fig. 1
A). We first examined whether
different CpG ODNs and poly(I:C) prevent pre-DC2 from dying. We used
three types of CpG ODNs: 1) 2006, which up-regulates the expression of
costimulatory molecules on human blood DC (7) and B cells
(24); 2) AAC-30 and GAC-30, which have palindromic CpG
motifs and stimulate human PBMC (10) and mouse spleen
cells (11) to produce type I IFN; and 3) 1668, which
stimulates mouse DC to express high levels of costimulatory molecules
and to produce proinflammatory cytokines TNF-, IL-6, and IL-12
(6).
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A, 1 µM CpG ODN 2006 efficiently blocked
the death of pre-DC2. The same concentration of control CpG ODN 2117
having the same sequence except for methylated cytosines blocked the
death of pre-DC2 to a lesser extent than 2006 (Fig. 1A). In
the presence of a lower concentration (0.1 µM) of 2117, most pre-DC2
died, whereas a significant number of pre-DC2 survived in the presence
of 0.1 µM 2006 (Fig. 1A). These are consistent with the
finding that methylation of cytosine residues significantly diminishes
immunostimulatory activity of CpG DNA (7). Another group
of CpG ODNs, AAC-30 and GAC-30, also maintained the survival of
pre-DC2, while ACC-30, which has been shown to lack the ability to
induce human PBMC to produce type I IFN (10), was less
efficient (Fig. 1A). Although 1 µM CpG ODN 1668 has been
shown to activate mouse DC (6), the same concentration of
1668 did not maintain the survival of pre-DC2 (data not shown). This is
consistent with the finding that CpG DNAs with strong stimulatory
activity in the mouse system does not necessarily activate human immune
cells (24, 25). In contrast to the CpG ODNs
immunostimulatory for human cells, poly(I:C) did not maintain the
survival of pre-DC2 (Fig. 1A).
The up-regulation of CD80 and CD86 expression on pre-DC2 is a hallmark
of their differentiation into DC (22, 23). Unmethylated
CpG ODN 2006 and methylated CpG ODN 2117 (1 µM) strongly up-regulated
the expression of CD80 and CD86 (Fig. 1B). AAC-30 and GAC-30
also up-regulated CD80 and CD86, albeit to a lesser extent than 2006
and 2117 (Fig. 1B).
Taken together, these data indicate that CpG ODNs containing appropriate sequences efficiently maintain the survival of pre-DC2 and induce them to differentiate into DC. In marked contrast, poly(I:C) does not stimulate pre-DC2 to survive and differentiate into DC.
Distinct CpG ODNs, but not poly(I:C), induce pre-DC2 to produce
IFN-
Next we examined whether CpG ODNs and poly(I:C) induce pre-DC2 to
produce IFN-. Although 2006 strikingly up-regulated CD80 and CD86
(Fig. 1B), this CpG ODN as well as 2117 and 1668 did not
induce pre-DC2 to produce detectable levels of IFN- (Fig. 2). In contrast, AAC-30 and GAC-30
induced pre-DC2 to produce large amounts of IFN- (AAC-30 508–1806
pg/ml; GAC-30 931–1362 pg/ml; n = 3; Fig. 2). ACC-30
induced pre-DC2 to produce much smaller amounts of IFN- (18–161
pg/ml; n = 3; Fig. 2). None of the CpG ODNs used here
induced CD11c+ DC and monocytes to produce
detectable levels of IFN- (data not shown). In line with the finding
that poly(I:C) did not maintain the survival of pre-DC2 (Fig. 1A), this reagent did not induce pre-DC2 to produce a
detectable level of IFN- (Table I).
These data indicate that ODNs containing particular CpG motifs, but not
poly(I:C), induce pre-DC2 to produce IFN-.
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and IL-12 and to undergo maturation
Although poly(I:C) did not induce pre-DC2 to survive (Fig. 1A) or to produce IFN- (Table I), this reagent has been
shown to induce human monocyte-derived DC to mature and to produce
IL-12 (8, 9). Thus, we asked whether poly(I:C) stimulates
CD11c+ myeloid DC (26) to produce
type I IFN and IL-12 and to undergo maturation. As shown in Table I,
poly(I:C) induced CD11c+ DC, but not pre-DC2 or
monocytes, to produce small, but significant, amounts of IFN-
(24.1–97.9 pg/ml; n = 3), IFN- (33.6–166.5 pg/ml;
n = 3), and IL-12 (17.7–137.7 pg/ml; n
= 4). Poly(I:C)-stimulated fibroblasts produced similar amounts of
IFN- (28.6–48.5 pg/ml; n = 2; Table I). Poly(I:C)
strongly up-regulated the expression of CD80 and CD86 on
CD11c+ DC during 24-h culture (Fig. 3). Thus, poly(I:C) stimulates
CD11c+ myeloid DC, but not pre-DC2, to produce
type I IFN and IL-12 and to become mature DC.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hartmann et al. screened an extensive series of CpG ODNs to find those
with the highest immunostimulatory activity for human cells (24, 27). They and others found that CpG ODN 2006 most potently
activates human B cells (24), monocytes (25),
and DC (7). In line with these findings, 2006 induced
marked up-regulation of CD80 and CD86 on pre-DC2. However, this CpG ODN
did not induce pre-DC2 to produce detectable levels of IFN-. In
contrast, another class of CpG ODNs, AAC-30 and GAC-30, which have been
shown to induce human PBMC (10) and mouse spleen cells
(11) to produce type I IFN, induced pre-DC2 to produce
IFN-. On the other hand, monocytes or CD11c+
DC did not produce detectable levels of IFN- in response to 2006,
AAC-30, or GAC-30. These data suggest that 1) pre-DC2 is the cell type
that produces IFN- in response to CpG DNAs; and that 2) it is
important to select CpG DNAs containing particular sequences to induce
pre-DC2 to produce IFN-. In addition, the finding that 2006 induced
pre-DC2 to up-regulate CD80 and CD86, but not to produce IFN-,
suggests that CpG DNA may induce pre-DC2 to differentiate into DC and
to produce IFN- through distinct signaling pathways.
Previous studies showed that methylation of cytosines in the CpG motifs abrogates the activity of CpG DNA to induce B cell proliferation (28) and NK cell activation (29). In this study, however, ODN 2117 containing methylated cytosines up-regulated CD80 and CD86 as strongly as ODN 2006 containing unmethylated CpG motifs, although 2117 did not support the survival of pre-DC2 as well as 2006 did. These data indicate that the methylation of cytosines abrogates the activity of CpG ODN 2006 only partially. It has been shown that ODNs with methylated CpG have a diminished, but significant, level of IFN-inducing capacity when encapsulated in liposomes (30). In addition, inverting CpG to GpC reduces, but does not totally abrogate, the activity of ODNs (including 1668 and 2006) to induce B cell proliferation and the up-regulation of costimulatory molecules (25). These findings suggest that although the presence of unmethylated CpG is most important for the optimal activity of immunostimulatory ODNs, those having appropriate flanking sequences can retain residual activity even without unmethylated CpG.
Our data suggest that CD11c+ DC is the only blood
cell type that produces a significant amount of type I IFN in response
to poly(I:C). CD11c+ DC and fibroblasts produced
similar levels of IFN- per cell. Since the number of fibroblasts in
tissues is probably greater than that of CD11c+
DC, the main producers of type I IFN in response to poly(I:C) and dsRNA
may be fibroblasts, not blood cells, as has been shown (13, 14). It has recently been shown that poly(I:C) induces the
maturation of monocyte-derived immature DC (8, 9). Whereas
CD11c+ DC appear to be myeloid-derived DC because
they express myeloid markers (26), pre-DC2-derived DC may
be lymphoid-derived DC because pre-DC2 lack myeloid markers
(26) and express mRNA of pre-T receptor -chain
(31). Thus, poly(I:C) may stimulate myeloid-derived, but
not lymphoid-derived, DC.
CpG DNA has pleiotropic effects on the immune system through activating
APC, i.e., B cells, macrophages, and DC (4). In
particular, a strong Th1-inducing effect of CpG DNA makes it a
promising immunological adjuvant to treat infectious diseases
(32), cancers (33), and allergic diseases
(34). It is conceivable that type I IFN induced by CpG DNA
contributes to the immunostimulatory effects of CpG DNA through various
mechanisms, such as enhancing NK cell activity (11),
inducing T cell activation (16), and enhancing IFN-
production by T cells (18). Therefore, CpG ODNs that
induce pre-DC2 to produce type I IFN may be suitable reagents for
clinical application. DNase-resistant phosphorothioate forms of AAC-30
and GAC-30 do not have a type I IFN-inducing effect on pre-DC2 (N.
Kadowaki, unpublished observations). Designing phosphorothioate forms
of CpG ODNs having such an effect may be an important future direction
for CpG immunology.
The molecular mechanisms by which the innate immune system recognizes
microbial components are a major topic of current immunology
(35). Although both CpG DNA (36, 37) and
dsRNA (38) activate NF-
B and Jun
NH2-terminal kinase, upstream signaling pathways
were shown to be different; CpG DNA, but not dsRNA, triggers a myeloid
differentiation marker-88- and TNF receptor-associated
factor-6-dependent pathway (39). The system we have
developed here provides an opportunity to identify the different
receptors involved in the recognition of CpG DNA vs dsRNA, which are
possibly members of the Toll-like receptor family
(40).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Norimitsu Kadowaki, Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
3 Abbreviations used in this paper: DC, dendritic cells; ODN, oligodeoxynucleotide; poly(I:C), polyinosinic-polycytidylic acid; IPC, natural IFN--producing cells; pre-DC2, type 2 dendritic cell precursors.
Received for publication August 24, 2000. Accepted for publication November 27, 2000.
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S. Pichyangkul, K. Yongvanitchit, U. Kum-arb, H. Hemmi, S. Akira, A. M. Krieg, D. G. Heppner, V. A. Stewart, H. Hasegawa, S. Looareesuwan, et al. Malaria Blood Stage Parasites Activate Human Plasmacytoid Dendritic Cells and Murine Dendritic Cells through a Toll-Like Receptor 9-Dependent Pathway J. Immunol., April 15, 2004; 172(8): 4926 - 4933. [Abstract] [Full Text] [PDF]
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N. Chaput, N. E. C. Schartz, F. Andre, J. Taieb, S. Novault, P. Bonnaventure, N. Aubert, J. Bernard, F. Lemonnier, M. Merad, et al. Exosomes as Potent Cell-Free Peptide-Based Vaccine. II. Exosomes in CpG Adjuvants Efficiently Prime Naive Tc1 Lymphocytes Leading to Tumor Rejection J. Immunol., February 15, 2004; 172(4): 2137 - 2146. [Abstract] [Full Text] [PDF]
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C. Asselin-Paturel, G. Brizard, J.-J. Pin, F. Briere, and G. Trinchieri Mouse Strain Differences in Plasmacytoid Dendritic Cell Frequency and Function Revealed by a Novel Monoclonal Antibody J. Immunol., December 15, 2003; 171(12): 6466 - 6477. [Abstract] [Full Text] [PDF]
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A. Izaguirre, B. J. Barnes, S. Amrute, W.-S. Yeow, N. Megjugorac, J. Dai, D. Feng, E. Chung, P. M. Pitha, and P. Fitzgerald-Bocarsly Comparative analysis of IRF and IFN-alpha expression in human plasmacytoid and monocyte-derived dendritic cells J. Leukoc. Biol., December 1, 2003; 74(6): 1125 - 1138. [Abstract] [Full Text]
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 E. Hartmann, B. Wollenberg, S. Rothenfusser, M. Wagner, D. Wellisch, B. Mack, T. Giese, O. Gires, S. Endres, and G. Hartmann Identification and Functional Analysis of Tumor-Infiltrating Plasmacytoid Dendritic Cells in Head and Neck Cancer Cancer Res., October 1, 2003; 63(19): 6478 - 6487. [Abstract] [Full Text] [PDF]
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F. Elias, J. Flo, R. A. Lopez, J. Zorzopulos, A. Montaner, and J. M. Rodriguez Strong Cytosine-Guanosine-Independent Immunostimulation in Humans and Other Primates by Synthetic Oligodeoxynucleotides with PyNTTTTGT Motifs J. Immunol., October 1, 2003; 171(7): 3697 - 3704. [Abstract] [Full Text] [PDF]
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L. Beloeil, M. Tomkowiak, G. Angelov, T. Walzer, P. Dubois, and J. Marvel In Vivo Impact of CpG1826 Oligodeoxynucleotide on CD8 T Cell Primary Responses and Survival J. Immunol., September 15, 2003; 171(6): 2995 - 3002. [Abstract] [Full Text] [PDF]
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M. Matsumoto, K. Funami, M. Tanabe, H. Oshiumi, M. Shingai, Y. Seto, A. Yamamoto, and T. Seya Subcellular Localization of Toll-Like Receptor 3 in Human Dendritic Cells J. Immunol., September 15, 2003; 171(6): 3154 - 3162. [Abstract] [Full Text] [PDF]
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L. Ping, A. Asai, A. Okada, K. Isobe, and H. Nakajima Dramatic increase of telomerase activity during dendritic cell differentiation and maturation J. Leukoc. Biol., August 1, 2003; 74(2): 270 - 276. [Abstract] [Full Text] [PDF]
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J. D. Marshall, K. Fearon, C. Abbate, S. Subramanian, P. Yee, J. Gregorio, R. L. Coffman, and G. Van Nest Identification of a novel CpG DNA class and motif that optimally stimulate B cell and plasmacytoid dendritic cell functions J. Leukoc. Biol., June 1, 2003; 73(6): 781 - 792. [Abstract] [Full Text] [PDF]
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G. de la Rosa, N. Longo, J. L. Rodriguez-Fernandez, A. Puig-Kroger, A. Pineda, A. L. Corbi, and P. Sanchez-Mateos Migration of human blood dendritic cells across endothelial cell monolayers: adhesion molecules and chemokines involved in subset-specific transmigration J. Leukoc. Biol., May 1, 2003; 73(5): 639 - 649. [Abstract] [Full Text] [PDF]
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M. Kerkmann, S. Rothenfusser, V. Hornung, A. Towarowski, M. Wagner, A. Sarris, T. Giese, S. Endres, and G. Hartmann Activation with CpG-A and CpG-B Oligonucleotides Reveals Two Distinct Regulatory Pathways of Type I IFN Synthesis in Human Plasmacytoid Dendritic Cells J. Immunol., May 1, 2003; 170(9): 4465 - 4474. [Abstract] [Full Text] [PDF]
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I. Teige, A. Treschow, A. Teige, R. Mattsson, V. Navikas, T. Leanderson, R. Holmdahl, and S. Issazadeh-Navikas IFN-{beta} Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis J. Immunol., May 1, 2003; 170(9): 4776 - 4784. [Abstract] [Full Text] [PDF]
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A. Yonezawa, R. Morita, A. Takaori-Kondo, N. Kadowaki, T. Kitawaki, T. Hori, and T. Uchiyama Natural Alpha Interferon-Producing Cells Respond to Human Immunodeficiency Virus Type 1 with Alpha Interferon Production and Maturation into Dendritic Cells J. Virol., March 15, 2003; 77(6): 3777 - 3784. [Abstract] [Full Text] [PDF]
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H. Tsujimura, T. Tamura, and K. Ozato* Cutting Edge: IFN Consensus Sequence Binding Protein/IFN Regulatory Factor 8 Drives the Development of Type I IFN-Producing Plasmacytoid Dendritic Cells J. Immunol., February 1, 2003; 170(3): 1131 - 1135. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Kanto, T. Tatsumi, V. Groh, T. Spies, T. Miyagi, T. Suzuki, Y. Sasaki, and N. Hayashi Critical Role of MHC Class I-Related Chain A and B Expression on IFN-{alpha}-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection J. Immunol., February 1, 2003; 170(3): 1249 - 1256. [Abstract] [Full Text] [PDF]
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R. Takauji, S. Iho, H. Takatsuka, S. Yamamoto, T. Takahashi, H. Kitagawa, H. Iwasaki, R. Iida, T. Yokochi, and T. Matsuki CpG-DNA-induced IFN-{alpha} production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors J. Leukoc. Biol., November 1, 2002; 72(5): 1011 - 1019. [Abstract] [Full Text] [PDF]
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M.-C. Rissoan, T. Duhen, J.-M. Bridon, N. Bendriss-Vermare, C. Peronne, B. d. S. Vis, F. Briere, and E. E. M. Bates Subtractive hybridization reveals the expression of immunoglobulinlike transcript 7, Eph-B1, granzyme B, and 3 novel transcripts in human plasmacytoid dendritic cells Blood, October 16, 2002; 100(9): 3295 - 3303. [Abstract] [Full Text] [PDF]
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Y. Osugi, S. Vuckovic, and D. N. J. Hart Myeloid blood CD11c+ dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes Blood, September 26, 2002; 100(8): 2858 - 2866. [Abstract] [Full Text] [PDF]
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D. Forman, R. M. Welsh, T. G. Markees, B. A. Woda, J. P. Mordes, A. A. Rossini, and D. L. Greiner Viral Abrogation of Stem Cell Transplantation Tolerance Causes Graft Rejection and Host Death by Different Mechanisms J. Immunol., June 15, 2002; 168(12): 6047 - 6056. [Abstract] [Full Text] [PDF]
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T. Ito, R. Amakawa, T. Kaisho, H. Hemmi, K. Tajima, K. Uehira, Y. Ozaki, H. Tomizawa, S. Akira, and S. Fukuhara Interferon-{alpha} and Interleukin-12 Are Induced Differentially by Toll-like Receptor 7 Ligands in Human Blood Dendritic Cell Subsets J. Exp. Med., June 3, 2002; 195(11): 1507 - 1512. [Abstract] [Full Text] [PDF]
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H. J. Cho, T. Hayashi, S. K. Datta, K. Takabayashi, J. H. Van Uden, A. Horner, M. Corr, and E. Raz IFN-{alpha}{beta} Promote Priming of Antigen-Specific CD8+ and CD4+ T Lymphocytes by Immunostimulatory DNA-Based Vaccines J. Immunol., May 15, 2002; 168(10): 4907 - 4913. [Abstract] [Full Text] [PDF]
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P. Riedl, D. Stober, C. Oehninger, K. Melber, J. Reimann, and R. Schirmbeck Priming Th1 Immunity to Viral Core Particles Is Facilitated by Trace Amounts of RNA Bound to Its Arginine-Rich Domain J. Immunol., May 15, 2002; 168(10): 4951 - 4959. [Abstract] [Full Text] [PDF]
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V. Hornung, S. Rothenfusser, S. Britsch, A. Krug, B. Jahrsdorfer, T. Giese, S. Endres, and G. Hartmann Quantitative Expression of Toll-Like Receptor 1-10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG Oligodeoxynucleotides J. Immunol., May 1, 2002; 168(9): 4531 - 4537. [Abstract] [Full Text] [PDF]
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W. Barchet, M. Cella, B. Odermatt, C. Asselin-Paturel, M. Colonna, and U. Kalinke Virus-induced Interferon {alpha} Production by a Dendritic Cell Subset in the Absence of Feedback Signaling In Vivo J. Exp. Med., February 19, 2002; 195(4): 507 - 516. [Abstract] [Full Text] [PDF]
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D. Verthelyi, R. T. Kenney, R. A. Seder, A. A. Gam, B. Friedag, and D. M. Klinman CpG Oligodeoxynucleotides as Vaccine Adjuvants in Primates J. Immunol., February 15, 2002; 168(4): 1659 - 1663. [Abstract] [Full Text] [PDF]
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C. Buelens, E. J. Bartholome, Z. Amraoui, M. Boutriaux, I. Salmon, K. Thielemans, F. Willems, and M. Goldman Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties Blood, February 1, 2002; 99(3): 993 - 998. [Abstract] [Full Text] [PDF]
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A. Dzionek, Y. Sohma, J. Nagafune, M. Cella, M. Colonna, F. Facchetti, G. Gunther, I. Johnston, A. Lanzavecchia, T. Nagasaka, et al. BDCA-2, a Novel Plasmacytoid Dendritic Cell-specific Type II C-type Lectin, Mediates Antigen Capture and Is a Potent Inhibitor of Interferon {alpha}/{beta} Induction J. Exp. Med., December 17, 2001; 194(12): 1823 - 1834. [Abstract] [Full Text] [PDF]
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P.-O. Vidalain, O. Azocar, H. Yagita, C. Rabourdin-Combe, and C. Servet-Delprat Cytotoxic Activity of Human Dendritic Cells Is Differentially Regulated by Double-Stranded RNA and CD40 Ligand J. Immunol., October 1, 2001; 167(7): 3765 - 3772. [Abstract] [Full Text] [PDF]
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 L. Farkas, K. Beiske, F. Lund-Johansen, P. Brandtzaeg, and F. L. Jahnsen Plasmacytoid Dendritic Cells (Natural Interferon- {{alpha}}/{beta}-Producing Cells) Accumulate in Cutaneous Lupus Erythematosus Lesions Am. J. Pathol., July 1, 2001; 159(1): 237 - 243. [Abstract] [Full Text] [PDF]
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