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* Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy; and
Viral Oncology, Centre National de la Recherche Scientifique, Villejuif, France
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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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Type I IFNs are cytokines spontaneously expressed at low levels under
physiologic conditions (3) whose expression is highly
enhanced soon after cell exposure to viruses or other stimuli
(4). Although first characterized as potent antiviral
molecules, type I IFNs are also endowed with immunoregulatory
activities, and their important role in linking innate and adaptive
immune responses has been unraveled (5, 6). A number of
reports have recently demonstrated a profound effect of these cytokines
on DC maturation, survival, and function. In this regard it has been
shown that type I IFNs (in combination with GM/CSF) rapidly induced the
differentiation of monocytes into partially mature DCs (mDCs) endowed
with potent functional activities both in vitro and in vivo (7, 8). Likewise, IFN-
has been described to act as a potent
maturation factor for CD11c+ DCs (myeloid DCs),
directly purified from the peripheral blood (9) and to
enhance the terminal differentiation of
CD34+-derived DCs (10). Moreover,
type I IFNs have been shown to act as adjuvants in the promotion of
humoral immune responses through stimulation of DCs (11).
On the other hand, a negative role of type I IFNs in the functional
maturation of DCs induced by pro-inflammatory cytokines has also been
described (12, 13).
Type I IFNs exert their biological activity through a broadly expressed heterodimeric receptor composed of the IFNAR1 and IFNAR2 subunits, whose mutual interaction activates a series of intracellular signaling molecules (14) The major signal transduction pathway used by type I IFNs is triggered upon receptor binding by the receptor-associated tyrosine kinases Janus kinase type 1 (JAK1) and tyrosine kinase type 2 (Tyk2). These kinases are activated by tyrosine auto/cross-phosphorylation and phosphorylate a number of substrates. Among them, a pivotal role is played by the transcriptional factors of the STAT family. Although STAT-1 and -2 are considered the major factors mediating type I IFN signaling, it has been reported that STAT-3 and, in humans, STAT-4 can be activated in response to these cytokines (15, 16).
Despite the growing evidence showing the importance of type I IFNs in
the development, survival, and functional activities of DCs, no studies
are currently available on the expression and signaling activity of
type I IFN receptors during the differentiation/maturation of these
cells. Moreover, although many of the stimuli promoting DC terminal
maturation are known to induce the production of type I IFNs, the role
of these endogenously produced IFNs in the modulation of DC functions
is still poorly studied. In this study we report that upon LPS-induced
maturation, DCs show a greatly impaired responsiveness to IFN-
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which correlated with a marked reduction of the expression of
both IFN receptor subunits. Down-modulation of receptor chains was only
partially mediated by ligand-induced receptor internalization
consequent to LPS-stimulated type I IFN secretion.
Overall, these data indicate that DCs strictly modulate their responsiveness to type I IFNs as part of their maturation program, strongly supporting the importance of the IFN system for the regulation of DC physiology.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monocytes were isolated from the peripheral blood of healthy
donors by counterflow centrifugal elutriation and were further purified
by depleting the nonmonocytic population by immunomagnetic beads
selection (MACS monocyte isolation kit from Miltenyi Biotec, Auburn,
CA) using the manufacturer’s procedure. To obtain immature DCs (iDCs),
monocytes were cultured at 1 x 106 cells/ml
in RPMI 1640 (Life Technologies, Gaithersburg, MD) medium containing
10% FBS supplemented with 50 ng/ml recombinant human GM-CSF and 500
U/ml recombinant human IL-4. Both cytokines were provided by
Schering-Plough (Dardilly, France). GM-CSF and IL-4 were added to the
cultures every 2–3 days. On days 4–6, iDCs were induced to final
maturation by adding LPS (200 ng/ml; Sigma-Aldrich, St. Louis, MO) and
were harvested 24 h later. In some experiments DCs were generated
by culturing monocytes in the presence of GM-CSF (50 ng/ml) and
IFN-2b (PeproTech, Rocky Hill, NJ). To neutralize type I IFNs during
the course of LPS-induced maturation, the following Abs were used:
anti-IFNAR1 mAb 64G12 (20 µg/ml) (17, 18) or a
mixture of sheep anti-human IFN- and sheep anti-IFN-
(PBL; Biomedical Laboratories, New Brunswick, NJ) Abs, each at the
concentration of 200 neutralizing units/ml. One neutralizing unit is
defined as the amount of Ab that reduces 10 IU/ml IFN to 1 IU/ml.
Type I IFN determination
Type I IFNs secreted in culture supernatants were measured using
a cytopathic effect reduction assay with HeLa cells (1 x
104 cells/well in 96-well microplates) and
vesicular stomatitis virus at a multiplicity of infection of 0.1
PFU/cell as challenge virus. Human IFN- reference standard
(Ga23- 902-530; National Institutes of Health, Bethesda, MD) was
used at a dilution of 500 IU/ml. The sensitivity of the assay ranged
from 5 to 15 IU/ml.
FACS analysis of DC surface phenotype
Cell staining was performed using FITC-conjugated mAbs (BD PharMingen, San Diego, CA). The following mAbs were used: CD14 (M5E2), CD1a (HI149), CD80 (L307.4), CD86 (2331), CD83 (HB15e), HLA-DR (G46-6), and CD40 (5C3). Briefly, 1–2 x 105 cells were preincubated for 30 min on ice with PBS/10% human serum to block nonspecific Ig binding and then incubated for an additional 30 min with the appropriate mAb. Cells were washed in PBS/10% human serum, fixed in 1% formaldehyde, and analyzed with a FACS flow cytometer (BD Biosciences, Mountain View, CA).
FACS analysis of type I IFN receptor expression
Surface receptor expression was monitored by staining cells with anti-IFNAR1 64G12 mAb (17, 18) or anti-IFNAR2 mAb (Calbiochem, La Jolla, CA), followed by biotinylated polyclonal anti-mouse IgG Ab (BD PharMingen) and FITC-streptavidin (BD PharMingen). Before staining, cells were blocked with PBS, 50% human serum, and 10% FBS. At the end of each incubation, cells were washed with PBS/10% human serum. After FITC-streptavidin incubation, cells were fixed and analyzed as described above.
RT-PCR
The total RNA used for the RT reaction was extracted using the RNeasy Mini kit (Qiagen, Valencia, CA) according to the manufacturer’s instructions. RT-PCR analysis of IFNAR1, IFNAR2, and GAPDH was performed as previously described (19). IFNAR1 cDNA was amplified using primers 2 and 5 as described by Abramovich et al. (20) For IFNAR2 cDNA amplification, primers DN11 and DN12 were used as previously described (21). The sequence of GAPDH primers has been previously described (22).
Immunoblotting
For the immunoblotting analysis of STAT tyrosine
phosphorylation, cells were left untreated or were treated for 45 min
with different doses of IFN- (provided by Serono, Ardea, Italy),
washed three times with ice-cold PBS, and lysed in RIPA buffer (150 mM
NaCl, 50 mM Tris-Cl (pH 7.5), 1% Nonidet P-40, 0.5% sodium
deoxycholate, and 0.1% SDS) containing a cocktail of protease and
phosphatase inhibitors (10 µg/ml aprotinin, 10 µg/ml leupeptin, 2
µg/ml pepstatin, 2 mM PMSF, 2 mM NaF, and 0.4 mM
Na3VO4). The protein
concentration was determined using the Bio-Rad protein assay (Hercules,
CA) according to the manufacturer’s instructions. Forty micrograms of
lysate was boiled for 4 min in Laemmli sample buffer, fractionated on
an 8% SDS-PAGE, and electroblotted to nitrocellulose filter (Protran
BA 85, Schleicher & Schuell, Keene, NH). The following Abs were used
for the immunoblots: rabbit anti-phospho-STAT-1 (Y701) and rabbit
anti-phospho-STAT-2 (Y689) (Upstate Biotechnology, Lake Placid,
NY), rabbit anti-phospho-STAT-3 (Y705; Cell Signaling Technology,
Beverly, MA), and anti-STAT-1, -2, and -3 mAbs (Transduction
Laboratories, Lexington, KY). An ECL Western blot detection system
(Amersham, Piscataway, NJ) was used according to the manufacturer’s
instructions.
Immunoprecipitation
For IFNAR1 and IFNAR2 immunoprecipitation, cells were lysed with Nonidet P-40 lysis buffer (150 mM NaCl, 50 mM Tris-Cl (pH 8), 0.5% Nonidet P-40, 10% glycerol, 10 µg/ml aprotinin, 10 µg/ml leupeptin, 2 µg/ml pepstatin, and 2 mM PMSF). IFNAR1 and IFNAR2 were immunoprecipitated from 1 mg whole cell lysate with 10 µg anti-IFNAR1 64G12 mAb or 5 µg anti-IFNAR2 mAb (Calbiochem), respectively, followed by a mix of protein A and protein G (1/1)/Sepharose. The immunoprecipitates were resolved on SDS-PAGE, electroblotted, and subjected to Western blot analysis as described above. The following mAbs were used for detection: 64G12 and anti-IFNAR2 (Calbiochem).
MLR assay
MLR was performed in RPMI culture medium supplemented with 5% heat-inactivated normal human AB serum. Allogeneic T cells (1–2 x 105/well) were cultured for 5 days in 96-well culture microplates as responder cells with 1–20 x 103 stimulatory cells (DCs). [3H]Thymidine incorporation (sp. act., 5 Ci/mM; Amersham) was measured after a 16-h pulse with 0.5 µCi/well. Results are shown as mean counts per minute of triplicate determinations. [3H]Thymidine incorporation in negative control wells, with responder T cells, or with stimulators DCs alone was always <800 cpm.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human peripheral blood monocytes were cultured with GM-CSF/IL-4 to
generate iDCs. Incubation of these cells with LPS for an additional
24 h led to a significant up-modulation of cell surface markers,
such as CD80, CD86, HLA-DR, CD83, and CD40, indicating the acquisition
of the well-defined phenotype of mDCs (Table I
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-induced tyrosine phosphorylation of STAT family members,
which are among the most proximal targets of the receptor-associated
tyrosine kinases, rapidly activated upon IFN binding.
Fig. 1 (A and B)
shows the results of a representative experiment in which we analyzed
the in vivo tyrosine phosphorylation of STAT-1, -2, and -3 in response
to different doses of IFN- in iDCs and LPS-mDCs 24 h after
stimulation. In iDCs, a marked tyrosine phosphorylation of all STATs
analyzed was observed at low IFN- doses (ranging from 10 to 50
IU/ml), which only slightly increased at higher doses of this cytokine.
On the contrary, LPS-mDCs displayed a constitutive level of tyrosine
phosphorylation of both STAT-1, -2, and -3, which was not further
induced even upon stimulation with high IFN- concentrations (up to
>1000 IU/ml). Notably, a higher expression of STAT-1 was consistently
detected in LPS-mDCs with respect to iDCs.
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To gain insight into the mechanism(s) involved in the impaired
STAT activation by LPS-mDCs in response to IFN-, time-course
experiments were conducted to investigate the surface expression of
type I IFN receptor chains, IFNAR1 and IFNAR2, during LPS-induced DC
maturation. As shown in Fig. 2, a
remarkable percentage of iDCs (CD86low and
CD83-) expressed both receptor components.
However, as soon as 4 h after LPS stimulation, a marked reduction
in the surface expression of both receptor chains was observed,
concomitantly to a significant increase in CD86 and CD83 expression. At
later time points (8 and 24 h), the surface expression of IFNAR1
and IFNAR2 remained barely detectable, whereas a progressive increase
in the expression of costimulatory and maturation markers was
observed.
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To characterize the mechanism(s) responsible for the reduced
expression of type I IFN receptor chains at the plasma membrane, the
steady-state level of expression of the receptor subunits was evaluated
by immunoprecipitation assays. Both IFNAR1 and IFNAR2 are glycosylated
proteins that migrate with an apparent molecular mass of 110–150 kDa
(IFNAR1) and 90–100 kDa (IFNAR2), depending on the cell type. As shown
in Fig. 3A, the total content
of both IFN receptor subunits was severely reduced upon LPS-induced
maturation. To establish whether the marked reduction in the total
content of the IFN receptor chains was associated with a decreased
expression of the corresponding mRNA, we performed semiquantitative
RT-PCR analysis using RNA isolated from iDCs and LPS-mDCs. As shown in
Fig. 3B, comparable levels of IFNAR1 and IFNAR2 mRNA
accumulation were observed independently of the DC maturation
stage.
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LPS is a well-known type I IFN inducer in a variety of murine and
human cell models, including monocytes/macrophages and DCs (22, 23). Since it has been described that type I IFN binding to
their receptor induces IFNAR1 internalization and degradation
(24), we asked whether the LPS-induced type I IFNs could
be responsible for the down-modulation of the IFN receptor chains
observed during DC maturation. To this aim, we initially analyzed the
kinetics of type I IFN production by DCs stimulated with LPS. In our
experimental cell model iDCs did not secrete any detectable level of
biologically active type I IFNs (data not shown). On the contrary,
biologically active type I IFNs were detected in the culture
supernatant 4 h after LPS stimulation, reached a plateau at 8
h, and remained stable until 48 h poststimulation (Fig. 4). To discriminate between de novo
production and accumulation of these cytokines in the culture medium,
after supernatant collection 1, 2, 4, 8, and 24 h poststimulation,
cells were reseeded in the presence of LPS and cultured until 24 or
48 h from the first stimulation, when supernatants were collected
to measure the residual type I IFN production. As shown in Fig. 4, type
I IFN production was barely detectable between 8 and 24 h
poststimulation and was below detection limits between 24 and 48
h. These results suggest that type I IFN production is an early and
transient phenomenon, starting between 2 and 4 h after LPS
stimulation, peaking between 4 and 8 h, and rapidly extinguishing
between 8 and 24 h.
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- and
IFN--neutralizing Abs. As shown in Fig. 5, the marked reduction in the percentage
of cells expressing IFNAR1 or IFNAR2 observed in LPS-mDCs was only
partially reverted when LPS-induced type I IFNs were neutralized by
specific Abs. Notably, IFNAR2 expression appeared to be almost
completely independent of the presence of type I IFNs. No changes were
observed for IFNAR1 and IFNAR2 expression in cells cultured with a
control Ab (Fig. 5).
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We finally evaluated whether the LPS-induced endogenous type I
IFNs played a role in phenotypic and functional DC maturation. Immature
DCs were stimulated to undergo terminal maturation by LPS in the
presence of Abs directed to the IFNAR1 subunit or in the presence of a
control Ab. As shown in Fig. 6A, neutralization of the
biological activity of endogenous type I IFNs did not result in any
significant phenotypic change as the same pattern of surface marker
expression was found independently of the presence of the
anti-IFNAR1 Ab. Similar results were obtained when LPS maturation
occurred in the presence of a mixture of Abs directed to IFN- and
IFN- (data not shown). To exclude that the lack of effect on the
LPS-induced DC phenotypic maturation could result from incomplete
blockage of IFN activity, DCs were derived from monocytes cultured with
GM-CSF and IFN- in the presence or the absence of the specific Ab.
As previously described, this experimental procedure leads to the
generation of partially mature DCs expressing CD83 and exhibiting
marked allostimulatory properties (7). As shown in Fig. 6B, the addition of anti-IFNAR1 Ab to GM-CSF/IFN-
monocyte cultures completely reversed the IFN-induced up-modulation of
CD86 and CD83 as well as the down-modulation of CD14. The addition of a
control Ab had no effect on the phenotypic maturation induced by
IFN-.
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, at all stimulator/responder ratios,
LPS-mDCs exhibited a higher capacity to stimulate the proliferation of
allogeneic lymphocytes than iDCs. LPS-mDCs generated in the presence of
Ab to IFNAR1 showed a similar allostimulatory capacity with respect to
LPS-mDCs derived in the absence of the Ab. No differences were observed
when LPS-mDCs were generated in the presence of a control Ab with
respect to control cultures (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in iDCs, whereas no inducible phosphorylation of
any of these STATs was detected in LPS-mDCs. Moreover, STAT-1, -2, and
-3 were constitutively activated in LPS-mDCs. These observations do not
necessarily imply that DC maturation results in the complete loss of
type I IFN sensitivity, but clearly indicate that the capacity of mDCs
to respond to this cytokine by activating the relevant STATs is
markedly reduced. This could be due to the fact that upon LPS
stimulation a number of cytokines, including type I IFNs, are induced,
many of which signal through the JAK/STAT pathway. This massive
activation of STATs could transiently exhaust the capacity of mDCs to
respond to cytokines through these transduction factors.
Cytokine-mediated JAK/STAT signaling pathways have been little studied
in monocyte-derived human DCs. Interestingly, it has been reported that
LPS-mDCs fail to activate STAT-1 and -3 in response to IL-10
(25) and become unresponsive to IFN-
by down-regulating
membrane expression of IFN-R1 (26), suggesting that
modulation of receptor expression and/or STAT activation may represent
common mechanisms to regulate cytokine responsiveness during the course
of DC maturation. Of note, IFN-, IL-10, and type I IFN receptors all
belong to the class II cytokine receptor family and share many
similarities in their structure (14). Moreover, both IL-10
and type I IFN receptors use the same JAK, Tyk2, and JAK1 for signal
transduction.
The absence of IFN-inducible STAT activation correlated with a
clear-cut down-modulation of the membrane expression of IFNAR1 and
IFNAR2, which occurred as early as 4 h after LPS treatment,
and with a severe reduction of the total intracellular content of both
receptor chains. The steady-state level of the corresponding
transcripts was not affected, suggesting that down-modulation is
mediated by post-transcriptional mechanisms. Although further studies
are needed to precisely define the step(s) at which receptor
down-modulation takes place, our data are consistent with the existence
of multiple regulatory mechanisms operating during the course of DC
maturation. In this regard, a common mechanism involved in the
modulation of cytokine and chemokine responsiveness is represented by
regulation of their receptor expression through autocrine
ligand-mediated loops. With respect to the IFN system, it has been
described that IFNAR1 is internalized and degraded following ligand
binding in Daudi cells (24). Moreover, we have
previously reported that IFNAR1 expression is regulated in human
monocytes/macrophages by differentiation-dependent post-transcriptional
mechanism(s) at least in part involving intracellular sequestration of
receptor components (19), and more recently, an increase
in type I IFN receptor binding sites has been observed upon in vitro
differentiation of CD34+ cells (27).
Finally, a role for the receptor-associated Tyk2 tyrosine kinase in
sustaining IFNAR1 expression has been demonstrated (28, 29). The finding that LPS-stimulated DCs rapidly and transiently
produce type I IFNs and that their maturation in the presence of a
mixture of neutralizing Abs directed to IFN- and IFN- only
partially restored IFNAR1 expression suggests that ligand-mediated
receptor internalization/degradation is one of the mechanisms involved
in the regulation of receptor expression during DC maturation. Although
IFNAR1 down-modulation cannot be explained by a reduced Tyk2 expression
in LPS-mDCs, as Tyk2 levels did not change upon LPS stimulation (data
not shown), a reduced intracellular availability of Tyk2 for IFNAR1,
due to competition with other cytokine receptor chains interacting with
Tyk2, cannot be excluded (29). Notably, the expression of
IFNAR1 and IFNAR2 appears to be independently regulated in this
cellular model. In fact, neutralization of the endogenous LPS-induced
type I IFNs did not rescue the surface expression of IFNAR2. To the
best of our knowledge, this is the first report describing the
differential regulation of type I IFN receptor chains and an
IFN-independent regulation of IFNAR2 expression. The observation that a
fine regulation of receptor expression occurs in DCs during the course
of their maturation provides a strong additional evidence on the
important role that type I IFNs may play in DC biology. In this regard,
it is tempting to speculate that this reduced type I IFN sensitivity
may contribute to protect mDCs from IFN-induced apoptosis. The
pro-apoptotic activity of type I IFNs on DCs has been independently
described by different groups (7, 8, 13) that observed a
reduced cell recovery after DC culture in the presence of type I IFNs.
In addition, it has been recently reported that type I IFNs in
combination with LPS induce apoptosis of monocyte-derived DCs
(30). Consistent with these reports we reproducibly
observed a reduced number of viable cells in DC cultures after 24
h of LPS stimulation with respect to control iDCs. Moreover, when
LPS-driven DC maturation took place in the presence of IFN-- and
IFN--neutralizing Abs, comparable numbers of viable cells were
recovered in the two maturation stages (data not shown). Protection
from type I IFN-induced apoptosis could be particularly important
in the inflamed lymph node when, upon arrival of plasmacytoid DCs
secreting large amounts of type I IFNs, the local concentrations of
these cytokines become very high (31, 32).
In the last few years the role of type I IFNs in the regulation of DC
development and functional maturation has been the object of an intense
investigation that yielded apparently contrasting results (7, 8, 9, 10, 12, 13, 23). Although many of the stimuli used for triggering DC
maturation are well-known type I IFN inducers, very few data are
available in the literature about the contribution of the endogenous
type I IFNs to the maturation process of monocyte-derived DCs. In this
regard, type I IFNs were characterized as soluble mediators released
following measles virus infection of monocyte-derived iDCs, which could
potentially contribute to DC maturation. However, their neutralization
only partially reversed the induction of CD86 observed in DC stimulated
with supernatants from infected cultures, and no effect was observed on
DC allostimulatory activity (33). We report here that
LPS-induced endogenous type I IFNs are dispensable for accomplishment
of the phenotypic and functional changes associated with DC maturation.
In fact, DCs induced to terminal maturation in the presence of
neutralizing Abs to the IFNAR1 receptor subunit or to IFN- and
IFN- exhibit a fully mature surface phenotype as well as allogeneic
T stimulatory activity, overlapping that of control LPS-mDCs. In
interpreting these data it should be taken into account that although
LPS-induced type I IFN production starts very early, it peaks between 4
and 8 h poststimulation. At this time point, down-modulation of
type I IFN receptors has already occurred, thus providing a potential
explanation for the lack of effect of these cytokines on at least some
phenotypic and functional changes associated with DC maturation.
A distinctive feature of DCs is their ability to perform different
functions depending on their maturation stage and localization. As
immature cells, iDCs are scattered throughout the body in nonlymphoid
organs, where they primarily exert a sentinel function, while
pathogen-activated mDCs migrate to lymph nodes, where they prime and
finely tune the primary responses of Ag-specific naive Th cells
(29). Cytokines and chemokines are key mediators of these
different activities, and it is becoming evident that they are produced
with distinct and strictly regulated kinetics, allowing their
sequential action in different microenvironments. For instance, the
release of pro-inflammatory cytokines (IL-6 and TNF-) and chemokines
(IL-8, macrophage inflammatory protein-1 and -1) starts in the
first 2–4 h of stimulation (34, 35) when DCs are probably
still resident in peripheral tissues. Together these soluble mediators
act on recruiting DC precursors at the site of infection. On the
contrary, IL-12 is undetectable until 10 h poststimulation, and
its production ends within 24 h. In keeping with its effect on
developing T cells, this cytokine may therefore be released when DCs
have reached the lymph nodes (34). The strict temporal
regulation of type I IFN production and responsiveness described in
this study is consistent with this scenario and add further important
clues to DC plasticity in tuning the immune response. The early
production of type I IFNs after pathogen encounter could contribute to
the establishment of a cytokine microenvironment promoting maturation
of the recruited DC precursors, and, in the case of viral infection,
limit viral spreading. This early production of type I IFNs appears
particularly important because the main type I IFN-producing cells, the
plasmacytoid DCs, are not thought to be present at sites of pathogen
entry (36). Later, within the inflamed lymph node, the
restricted temporal window of IL-12 (34) and IFN
production (both drop within 24 h after stimulation) could help to
dampen the initial Th1 response, thus preventing immunologically
mediated damage. Moreover, it could ensure the establishment of a pool
of unpolarized memory T cells. Finally, the reduced sensitivity of
myeloid mDCs to type I IFNs could prolong their survival in the lymph
node, thus enhancing their priming and tuning activity toward T
cells.
Maturation-associated changes in the DC responsiveness to soluble mediators, released early during the immune response, serve as relevant regulatory loops with important consequences for the final outcome of the immune response. Their knowledge mayhelp in designing optimal strategies for DC-based therapeutic interventions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Sandra Gessani, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail address: gessani{at}iss.it
3 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; JAK1, Janus kinase type 1; Tyk2, tyrosine kinase type 2; mDC, mature DC.
Received for publication March 20, 2002. Accepted for publication July 17, 2002.
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S. M. Best, K. L. Morris, J. G. Shannon, S. J. Robertson, D. N. Mitzel, G. S. Park, E. Boer, J. B. Wolfinbarger, and M. E. Bloom Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist J. Virol., October 15, 2005; 79(20): 12828 - 12839. [Abstract] [Full Text] [PDF]
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M. Del Corno, M. C. Gauzzi, G. Penna, F. Belardelli, L. Adorini, and S. Gessani Human Immunodeficiency Virus Type 1 gp120 and Other Activation Stimuli Are Highly Effective in Triggering Alpha Interferon and CC Chemokine Production in Circulating Plasmacytoid but Not Myeloid Dendritic Cells J. Virol., October 1, 2005; 79(19): 12597 - 12601. [Abstract] [Full Text] [PDF]
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 L. Conti, R. Casetti, M. Cardone, B. Varano, A. Martino, F. Belardelli, F. Poccia, and S. Gessani Reciprocal Activating Interaction Between Dendritic Cells and Pamidronate-Stimulated {gamma}{delta} T Cells: Role of CD86 and Inflammatory Cytokines J. Immunol., January 1, 2005; 174(1): 252 - 260. [Abstract] [Full Text] [PDF]
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M. C. Gauzzi, C. Purificato, K. Donato, Y. Jin, L. Wang, K. C. Daniel, A. A. Maghazachi, F. Belardelli, L. Adorini, and S. Gessani Suppressive Effect of 1{alpha},25-Dihydroxyvitamin D3 on Type I IFN-Mediated Monocyte Differentiation into Dendritic Cells: Impairment of Functional Activities and Chemotaxis J. Immunol., January 1, 2005; 174(1): 270 - 276. [Abstract] [Full Text] [PDF]
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L. Fantuzzi, C. Purificato, K. Donato, F. Belardelli, and S. Gessani Human Immunodeficiency Virus Type 1 gp120 Induces Abnormal Maturation and Functional Alterations of Dendritic Cells: a Novel Mechanism for AIDS Pathogenesis J. Virol., September 15, 2004; 78(18): 9763 - 9772. [Abstract] [Full Text] [PDF]
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M. Weber, C. Lange, W. Gunther, M. Franz, E. Kremmer, and H.-J. Kolb Minor Histocompatibility Antigens on Canine Hemopoietic Progenitor Cells J. Immunol., June 15, 2003; 170(12): 5861 - 5868. [Abstract] [Full Text] [PDF]
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