| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Institute of Experimental Immunology, Department of Pathology, University of Zürich, Zürich, Switzerland
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and TNF-
. In
contrast, IL-12-deficient mice showed impaired abilities to control
infection with the facultative intracellular bacterium Listeria
monocytogenes at early time points after infection. However, at
later time points of infection, IL-12-deficient mice were able to clear
infection. These findings may indicate that viruses are able to induce
type 1 T cell responses in the absence of IL-12 as opposed to some
bacterial or parasitical infections that are crucially dependent on the
presence of IL-12 for the induction of type 1 immune
responses. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
secretion (1, 4).
IL-12-dependent IFN- induction appears to be an important step in
macrophage activation, which was shown to be of biological relevance in
the generation of protective immunity against infection with
Mycobacterium tuberculosis (2) and in the
induction of a leishmaniocidal status of macrophages in
Leishmania major infection (3, 10, 11).
To evaluate the role of IL-12 for immune responses in viral infections,
IL-12-deficient mice on the C57BL/6 background were infected either
with noncytopathic lymphocytic choriomeningitis virus
(LCMV)3 or with cytopathic vesicular
stomatitis virus (VSV), and several parameters of virus-specific
immunity were assessed. In normal C57BL/6 mice LCMV infection induces
CD4+ T cells exhibiting a type 1 cytokine secretion pattern
(12). Interestingly, the cytokine secretion pattern
profile of LCMV-specific CD4+ T cells in IL-12-deficient
mice was identical to the one observed in C57BL/6 mice, indicating that
the induction of IFN- secretion by LCMV-specific CD4+ T
cells was not dependent on IL-12. In line with this, LCMV-specific IgG
responses upon infection of IL-12-deficient mice were predominantly of
the IgG2a isotype and thus identical to the IgG responses observed in
LCMV-infected C57BL/6 mice. Infection of IL-12-deficient mice with VSV
induced a neutralizing IgM, and IgG response and the VSV-specific IgG
response showed equivalent serum IgG2a/IgG1 ratios between
IL-12-deficient and normal mice.
Furthermore, LCMV- or VSV-infected IL-12-deficient or control mice were
equally well protected against challenge immunization with recombinant
vaccinia viruses expressing the LCMV- or VSV-derived glycoprotein.
Protection in this experimental setup is known to be mediated via
release of the type I cytokines IFN- and TNF- by
glycoprotein-specific T cells (13). These findings
indicate that the priming LCMV or VSV infection had induced
functionally active T cell responses of the type 1 phenotype.
In contrast to viral infections, IL-12-deficient mice showed reduced abilities to control infection with the intracellular bacteria Listeria monocytogenes at early time points after infection, most probably due to suboptimal activation of macrophages that are crucial in the early phase of the primary immune response against infection with L. monocytogenes (14, 15, 16).
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Inbred C57BL/6 (H-2b) mice were obtained from the breeding colony of the Institut für Zuchthygiene (Tierspital Zürich, Switzerland). The generation of mice deficient for the IL-12 P40 chain has been described previously (1). Mice were bred in a specific pathogen-free mouse house facility.
Viruses and bacteria
The LCMV isolate WE was originally provided by Dr. F. Lehmann-Grube (Hamburg, Germany) and grown on L929 cells (ATCC CRL 1) with a low multiplicity of infection. VSV indiana (Mudd-Summers isolate) seeds, originally obtained from D. Kolakofsky (University of Geneva), were grown on BHK-21 (ATCC CRL 8544) cells infected at low multiplicity of infection and plaqued on Vero cells.
Vaccinia virus expressing the glycoprotein of VSV was a generous gift of Dr. B. Moss (Laboratory of Viral Diseases, National Institutes of Health, Bethesda, MD) (17). Recombinant vaccinia virus expressing LCMV GP has been described (18). Recombinant viruses were grown at low multiplicity of infection on BSC cells and plaqued on BSC cells.
The recombinant baculovirus expressing the LCMV nucleoprotein has been previously described (19). The recombinant baculovirus was derived from nuclear polyhedrosis virus and was grown at 28°C in Spodoptera frugiperda cells in spinner cultures in TC-100 medium. Recombinant proteins were produced as previously described (20).
Listeria monocytogenes was originally obtained from B. Blanden (Canberra, Australia). It was cultured in trypticase soy broth (BBL Microbiology Systems, Cockeysville, MD), and overnight cultures were titrated on tryptose blood agar plates (Difco Laboratories, Detroit, MI).
T cell proliferation
Mice were immunized i.v. with 200 pfu LCMV-WE. Thirteen days later, CD4+ T cells were purified from spleen cell suspensions by MACS-sorting according to the protocol of the supplier (Miltenyi Biotec, Bergisch Gladbach, Germany). CD4+ T cells (1 x 105) were incubated in 96-wells with 3-fold serial dilutions of live LCMV (highest concentration, MOI = 1), peptide P13 (highest concentration, 5 µg/ml), peptide P61 (highest concentration, 5 µg/ml) or medium only in the presence of 6 x 105 irradiated (2000 cGy) C57BL/6 spleen cells for 3 days. Proliferation was assessed by incorporation of [3H]thymidine (1 µCi/well). P13 and P61 represent I-Ab-restricted T cell epitopes of the glycoprotein and nucleoprotein of LCMV that has been described elsewhere (21).
Cytokine analysis
Supernatants of proliferation assays as described above were
analyzed for IFN- content and IL-4 content (72 h after
restimulation). IFN- and IL-4 were assessed by ELISA as described
(12).
Adoptive transfer of naive TCR transgenic CD4+ T cells followed by challenge with live or UV-inactivated LCMV
CD4+ T cells were purified by MACS-sorting (Miltenyi Biotec) from spleen cell suspensions of naive TCR transgenic mice (Smarta) (22), and 5 x 106 CD4+ T cells were adoptively transferred into naive IL-12-deficient or control C57BL/6 recipients. Three days later recipient mice were infected intravenously with 200 pfu of LCMV. Control mice were not infected. Spleen cells were harvested 9 days after infection and either stained for the presence of TCR transgenic CD4+ T cells or stained for intracellular cytokine production.
Cytofluorometric analyses
The following mAbs were used for analysis: biotinylated 7G8,
specific for Vß8.3 (a gift from Dr. I. Förster, Ref.
23); phycoerythrin-conjugated B20.1, specific for V2
(purchased from PharMingen, San Diego, CA); fluorescein-conjugated
anti-IFN- or anti-TNF- (purchased from
PharMingen), and phycoerythrin-conjugated anti-IL-4
(purchased from PharMingen). Tricolor-conjugated streptavidin
or anti-CD4 were purchased from Caltag Laboratories (South San
Francisco, CA). Flow cytometry was performed on as FACSstar Plus flow
cytometer (Becton Dickinson, Mountain View, CA).
Intracellular cytokine stainings were performed according to the instructions of the supplier (PharMingen).
ELISA
The LCMV nucleoprotein-specific ELISA has been described previously (19). Ninety-six-well plates (Petra Plastik, Chur, Switzerland) were incubated with LCMV nucleoprotein (0.01 µg/well) in 0.1 M NaH2PO4 (pH 9.4) at 4°C. Plates were then preincubated with 2% BSA in PBS for 2 h and washed, and serial dilutions of serum samples (30-fold prediluted) were added to the wells and incubated for 90 min. Plates were washed and incubated with horseradish peroxidase-labeled goat anti-mouse IgG2a or IgG1 (Zymed, San Francisco, CA). After 90 min, plates were washed and developed with ABTS (5 mg of 2,2'-azino-di-3-ethyl-benzthiazolinsulfonate and 20 µl of H2O2 in 50 ml of NaHCO3, pH4). Optical densities were determined at 405 nm.
For the VSV-specific IgG subclass analysis, ELISA plates were coated with purified VSV (10 µg/ml), serial dilutions of 30-fold prediluted serum samples were added, and VSV-bound IgG was detected with horseradish peroxidase-labeled goat anti-mouse IgG1, IgG2a, or IgG2b Abs (Zymed).
Serum neutralization test
Neutralizing titers of sera were determined as described (24). Sera were prediluted 40-fold in supplemented MEM and heat-inactivated for 30 min at 56°C. Serial 2-fold dilutions were mixed with equal volumes of virus diluted to contain 500 pfu/ml. The mixture was incubated for 90 min at 37°C in an atmosphere containing 5% CO2. One hundred microliters of the serum-virus mixture were transferred onto Vero cell monolayers in 96-well plates and incubated for 1 h at 37°C. The monolayers were then overlaid with 100 µl of DMEM containing 1% methyl cellulose. After incubation for 24 h at 37°C, the overlay was removed and the monolayer was fixed and stained with 0.5% crystal violet. The highest dilution of the serum that reduced the number of plaques by 50% was taken as the neutralizing titer. To determine IgG titers, undiluted serum was first pretreated with an equal volume of 0.1 M 2-ME in saline (25).
Protection of mice from replication of recombinant vaccinia virus
Mice were immunized with 200 pfu of LCMV or with 2 x 106 pfu of VSV and challenged i.p. 20 days later with 5 x 106 pfu of recombinant vaccinia virus expressing LCMV glycoprotein (Vacc-G2) or expressing VSV-glycoprotein (Vacc-INDG). Vaccinia titers in ovaries were determined 5 days later as described previously (13). Titers are shown as log10 pfu per animal.
LCMV-specific CTL activity and determination of LCMV titers
IL-12-deficient and control mice were infected i.v. with 200 pfu of LCMV, and 8 days later spleen cell suspensions were prepared and tested for cytotoxic activity on peptide-pulsed (gp33, 1 µM) EL4 (H-2b) cells (26).
LCMV titers were determined in the spleen, liver, kidney, and blood of IL-12-deficient or control mice 4 and 8 days after i.v. infection with 200 pfu of LCMV as described previously (27).
Determination of bacterial titers
On the indicated days after inoculation the whole spleen or one lobe of the liver were harvested and homogenized. Bacterial titers were determined by plating out four serial 10-fold dilutions of organ suspensions on tryptose blood agar plates.
NK response
Ex vivo NK activity of spleen cells was determined 2 days after infection of IL-12-deficient mice or control mice with 1 x 106 pfu of LCMV-WE i.v. Spleen cell suspensions were tested on NK-sensitive YAC-1 target cells at the indicated effector to target ratios in a standard 5-h 51Cr release assay (26).
In vivo depletion of NK cells/in vivo neutralization
of IFN-
Depletion of NK cells was performed by i.v. administration of
the NK-depleting Ab TMß1 (28) or i.p. administration of
anti-NK1.1 mAb (29) 1 day before LCMV infection. In
vivo neutralization of IFN- was performed by daily i.p. injections
of anti-IFN- sheep serum (30). As a control, mice
were treated daily with normal sheep serum.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To evaluate the proliferative capacity of LCMV-specific
CD4+ T cells induced in IL-12 P40 chain-deficient mice
(P40-/-) and in control C57BL/6 mice, CD4+ T
cells were purified from spleen cell suspensions 13 days after LCMV
infection. CD4+ T cells were restimulated in vitro with
LCMV, with the LCMV GP-derived helper epitope peptide P13 or the LCMV
NP-derived helper epitope peptide P61 (21). Stimulation
indices are shown in Fig. 1A
and were equivalent for CD4+ T cells from LCMV-infected
IL-12-deficient or control mice. To analyze the cytokine secretion
patterns of LCMV-specific CD4+ T cells, supernatants of the
above described proliferation assays were collected at 24 h (for
IL-2 content) and 72 h (for IFN- and IL-4 contents) after in
vitro stimulation. Both LCMV-specific CD4+ T cells from
IL-12-deficient and control mice secreted similar amounts of IFN-,
whereas no IL-4 could be detected in both cases (Fig. 1B).
IL-2 secretion was also equivalent for LCMV-specific CD4+ T
cells from LCMV-infected IL-12-deficient and control mice (data not
shown). These findings indicate that IFN- production by
LCMV-specific CD4+ T cells occurs independently of IL-12
upon LCMV infection in vivo as opposed to immunizations with proteins
where IL-12 was shown to be instrumental for IFN- production
(1).
In vivo analysis of cytokine patterns produced by LCMV-specific CD4+ T cells upon LCMV infection
To visualize cytokine production by CD4+ T cells
activated specifically by LCMV, TCR transgenic T cells exhibiting
defined specificity for the LCMV GP-derived epitope P13
(22) were activated in vivo in IL-12-deficient or
IL-12-competent hosts upon LCMV infection. When CD4+ T
cells from naive transgenic mice were adoptively transferred into naive
C57BL/6 recipients, they clonally expanded and gained cytokine
expression only after activation by viral infection (22).
Clonally expanded TCR transgenic LCMV-specific CD4+ T cells
can be analyzed directly ex vivo for their cytokine production by means
of intracellular cytokine staining. Purified CD4+ T cells
(5 x 106) originating from naive Smarta TCR
transgenic mice (22) with specificity for the LCMV
GP-derived I-Ab-binding epitope P13 were adoptively
transferred into naive IL-12-deficient or normal C57BL/6 mice. Three
days later, recipient mice were infected i.v. with LCMV. Control
recipients were left untreated. Nine days after challenge, percentages
of TCR transgenic CD4+ T cells in spleens were determined
by FACS analysis. Cytokine production by TCR transgenic
CD4+ T cells was assessed by intracellular cytokine
staining for IFN-, TNF-, and IL-4; results are summarized in
Table I
. The first row shows percentages
of TCR transgenic T cells of total CD4+ T cells in the
spleen of immunized versus control recipients. TCR transgenic
CD4+ T cells had clonally expanded to significant levels at
day 9 after LCMV infection (40% V2+
Vß8.3+ T cells of total CD4+ T cells). The
lower three rows of Table I show the percentages of cytokine-producing
CD4+ V2+ T cells. In both
LCMV-infected IL-12-deficient and control mice, significant
numbers of TCR transgenic CD4+ T cells produced IFN-
(40% IFN--producing CD4+ V2+ T cells) or
TNF- (25% TNF--producing CD4+ V2+ T
cells), whereas no IL-4-producing transgenic T cells could be detected
(<1% IL-4-producing CD4+ V2+ T cells). In
the lower section of Table I representative FACS stainings are
shown.
|
staining
between IL-12-deficient and control mice; i.e., about 6–9% of TCR
nontransgenic CD4+ T cells stained positive for IFN-,
which is close to background levels. Thus, LCMV-specific TCR transgenic
CD4+ T cells were specifically activated in an
IL-12-deficient environment to produce type 1 but not type 2
cytokines. LCMV- and VSV-specific humoral responses in IL-12-deficient mice
To correlate the type 1 cytokine response elicited in
IL-12-deficient mice upon LCMV infection with the isotype patterns of
LCMV-specific IgG responses, IL-12-deficient and control mice were
infected with LCMV, and 20 days later LCMV NP binding IgG2a and IgG1
Abs were measured by ELISA (Fig. 2). A
predominant LCMV NP-specific IgG2a response was induced in both
IL-12-deficient and control mice, reflecting the induction of a type 1
CD4+ T cell response. However, if IL-12-deficient or
control mice were immunized s.c. with noninfectious UV-inactivated LCMV
in CFA, the predominant isotype of the LCMV NP-specific IgG response
was IgG1 in IL-12-deficient and control mice, indicating that the
phenotype of the CD4+ T cell response induced after
immunization with nonreplicating LCMV is different from the one after
infection with live LCMV. This is in contrast to observations made for
mouse hepatitis coronavirus (MHV) infection where infectious and
nonreplicating MHV were both predominantly inducing IgG Abs of the
IgG2a isotype (31).
|
Antiviral protection mediated by type 1 cytokines in IL-12-deficient mice
In some viral infections, T cell-secreted cytokines can directly
exhibit antiviral protective effector functions. Vaccinia virus
infection for example is resolved in mice by the direct antiviral
effects of the type 1 cytokines IFN- and TNF- (33, 34). Thus, T cell-secreted cytokine-mediated antiviral
protection can experimentally be assessed by challenge immunization of
either LCMV- or VSV-primed mice with recombinant vaccinia viruses
expressing either the LCMV GP (Vacc-G2) or the VSV G
(Vacc-INDG), respectively (13, 35). In the
case of LCMV-immune mice, LCMV GP-specific CD8+ T cells
mediate protection against challenge immunization with Vacc-G2 (Dr. T.
Kündig, unpublished data), whereas in the case of VSV-primed
mice, VSV G-specific CD4+ T cells confer protection against
challenge immunization with Vacc-INDG (35). In
both experimental systems, protection is mediated by T cell-secreted
type 1 cytokines rather than by direct T cell-mediated cytolytic
mechanisms (13, 35, 36). Thus, to address the question
whether antivirally protective type 1 T cell responses were induced in
the absence of IL-12, IL-12-deficient mice and control mice were
infected with either LCMV or VSV and 20 days later they were challenged
with Vacc-G2 or Vacc-INDG, respectively. Vaccinia titers
were determined 5 days after challenge in the ovaries (Fig. 4). Protection against challenge with
recombinant vaccinia virus indicated that the priming infection with
LCMV or VSV had induced protective type 1 T cell responses in both
IL-12-deficient and control mice.
|
To test for NK cell activation after LCMV infection,
IL-12-deficient mice and control mice were infected with 1 x
106 pfu of LCMV WE, and 2 days later ex vivo NK activity
was determined by lysis of the NK-sensitive target cell line YAC-1
(Fig. 5). NK effectors from
IL-12-deficient mice and from control C57BL/6 mice showed comparable
levels of YAC-1 cell lysis.
|
was possibly
involved in the generation of the Th1 phenotype of LCMV-specific
CD4+ T cells, naive TCR transgenic CD4+ T cells
were adoptively transferred into IL-12-deficient recipients or control
recipients that were either depleted of NK cells or left untreated. NK
cell depletion was functionally tested by the absence of YAC-1 killing
at day 2 after infection with high doses of LCMV-WE (data not shown).
Two different Abs were independently used for in vivo NK cell
depletion: Tmß1 and anti-NK1.1 (29). Recipients were
infected with LCMV, and the cytokine production pattern of the clonally
expanded TCR transgenic CD4+ T cells was analyzed by
intracellular cytokine staining and FACS analysis. Also, in the absence
of NK cells, LCMV TCR transgenic CD4+ T cells produced
significant amounts of IFN- and TNF- after activation by LCMV in
an IL-12-deficient recipient (Table II).
These results suggest that neither IL-12 nor NK cell-produced IFN-
are required for the induction of a type 1 phenotype in LCMV-specific
CD4+ T cells after LCMV infection.
|
is required for the induction of
LCMV-specific type 1 CD4+ T cells, IL-12-deficient mice and
control mice transfused with purified CD4+ T cells from
naive TCR transgenic mice were treated daily with IFN--neutralizing
sheep serum or as a control with normal sheep serum during the time
course of LCMV infection (30). Nine days after infection,
cytokine production patterns of clonally expanded CD4+ TCR
transgenic T cells were analyzed by intracellular cytokine staining
(Table III). In vivo neutralization of
IFN- showed little effect on the cytokine production pattern of TCR
tg CD4+ T cells transferred into C57BL/6 recipient mice
whereas it exhibited more pronounced effects on the cytokine production
patterns of the TCR tg CD4+ T cells transferred into
IL-12-deficient recipient mice. IFN- neutralization in
IL-12-deficient recipients resulted in partial impairment of IFN-
and TNF- production in clonally expanded TCR transgenic
CD4+ T cells with concomitant appearance of IL-4-producing
TCR transgenic CD4+ T cells. The induction of significant
numbers of IL-4-producing LCMV-specific CD4+ TCR transgenic
T cells in anti-IFN--treated IL-12-deficient mice but not in
anti-IFN--treated C57BL/6 mice suggests that IFN- plays an
important role for the induction of LCMV-specific type 1
CD4+ T cells in the absence of IL-12. However, in the
presence of IL-12 (C57BL/6 mice) anti-IFN- treatment does not
abrogate commitment of LCMV-specific CD4+ T cells towards
the type 1 phenotype after LCMV infection. The source of IFN- after
LCMV infection in IL-12-deficient mice driving type 1 CD4+
T cell development (not being NK cells as described above) remains to
be identified.
|
We analyzed whether impaired or delayed virus clearance due to suboptimal CTL induction or due to enhanced viral replication was observed in IL-12-deficient mice. Thus, IL-12-deficient and normal mice were infected with LCMV and viral titers were determined in blood, spleen, liver, and kidney 4 and 8 days later. No LCMV was detectable in blood, liver and kidney at day 4 or day 8 after infection (not shown). However, LCMV titers in the spleen were comparable at day 4 and day 8 after infection (Fig. 6A). Similarly, day 8 effector CTLs were comparably induced in IL-12-deficient and control mice (Fig. 6B). This is in agreement with previously published observations where it was shown that viral replication and CTL induction after LCMV infection were unaltered after in vivo neutralization of IL-12 (37).
L. monocytogenes clearance is impaired in IL-12-deficient mice
In the early phase of primary L. monocytogenes
infection in mice it has been shown that neutrophils and macrophages
play an important role to restrict bacterial replication and that the
cytokines IFN- and TNF- as well as reactive oxygen intermediates
produced by IFN--activated macrophages are essential for protection
(14, 15, 38). In contrast, later phases of primary
infections as well as secondary infections are mainly controlled by
specific (memory) CD8+ T cell responses (16, 39). It was of interest to compare the role of IL-12 in primary
L. monocytogenes infection as opposed to the above-described
viral infections, especially since IL-12 has been attributed an
important indirect (IFN--mediated) role in the activation process of
macrophages (2). Thus, IL-12-deficient and control mice
were inoculated intravenously with 600 live bacteria and bacterial
titers were determined in the spleen and in the liver 5 or 14 days
later (Fig. 7B). Listeria
titers at day 5 after inoculation were significantly higher in organs
of IL-12-deficient mice. In the spleen a 10-fold difference and in the
liver a 100-fold difference was observed between IL-12-deficient and
control mice. However, 14 days after inoculation IL-12-deficient mice
as well as C57BL/6 mice had cleared the bacteria from both the spleen
and the liver, suggesting that IL-12 played an important role in
controlling bacterial burden at early phases of infection but was not
necessary for eventual clearance of infection. To rule out the
possibility that the observed differences in bacterial titers 5 days
after infection were due to an altered dissemination of the bacteria in
IL-12-deficient mice or to differences in early infection with L.
monocytogenes, IL-12-deficient and C57BL/6 control mice were
inoculated i.v. with high doses of bacteria (7 x 105
cfu) and bacterial titers were determined in the blood 5 min later and
in the spleen and liver 1 h later. At these very early time points
after inoculation both IL-12-deficient and control mice exhibited
comparable bacterial titers (Fig. 7A). These results
demonstrate that IL-12 seems to play an important role in the
macrophage activation process required for resolution of primary
infection with L. monocytogenes.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
secretion in vitro
and was thus identical to the one observed in normal C57BL/6 mice after
LCMV infection (12). In line with this, in vivo analysis
of cytokine production by LCMV-specific TCR transgenic CD4+
T cells upon adoptive transfer into LCMV-infected IL-12-deficient
recipients showed that the type 1 cytokines IFN- and TNF- but not
IL-4 were produced by the transferred CD4+ T cells. Ig
isotype patterns of virus-specific Ab responses after infection of
IL-12-deficient mice with either LCMV or VSV were predominantly of the
IgG2a isotype, reflecting again the induction of a type 1 T cells
response after infection of IL-12-deficient mice with these viruses.
Antiviral protection mediated by secretion of type 1 cytokines by
virus-primed T cells did also not depend on the presence of IL-12. The
IL-12-independent induction of IFN--secreting CD4+ T
cells upon viral infections is thus in contrast to results obtained
with nonviral immunizations where IL-12 seemed to play a critical role
in this respect (1, 2, 3, 4, 5, 6, 7, 8, 9). The results described in this
report fully confirm previous findings by Orange and Biron
(37), which demonstrated that early IL-12 production is
not measurably induced upon LCMV infection and that in vivo
neutralization of IL-12 has no effect on early LCMV replication, on
induction of early NK cell cytotoxicity and on viral clearance on days
7 and 9 after infection. These earlier results suggested the existence
of IL-12-independent mechanisms for IFN- production and for T
cell-mediated control of viral infection (37). In
addition, Schijns et al. (31) demonstrated that
IL-12-deficient mice are able to mount polarized Th1 CD4+ T
cell responses upon infection with MVH, suggesting that at least
certain viruses may selectively induce IFN- production and type 1
cytokine responses in the absence of IL-12. Apparently, protein
immunizations or some infections with nonviral microorganisms seem to
require more subtle mechanisms controlling induction of the phenotype
of specific T cells. IL-12 production is normally observed in APCs such
as macrophages, B cells or dendritic cells (40, 41). It was
shown for macrophages that IL-12 production was only induced after
preactivation with IFN-, whereby IFN- is governing IL-12
production on the transcriptional level by activating the IL-12 p35 and
p40 promoters (42). Macrophage-secreted IL-12 seems to
operate then in a positive feedback mechanism enhancing IFN-
production by NK and T cells (43). This IFN--enhancing
positive feedback mechanism mediated by IL-12 is most probably not
required in viral infections because viruses are usually potent
inducers of IFN- in T cells and NK cells. The NK cells are usually
one of the first sources of IFN- production after viral infection
(44) and at later phases of infection activated
virus-specific T cells normally also produce IFN- (45).
Taking into account the observation that in vivo depletion of NK cells
in IL-12-deficient mice did not hamper the induction of LCMV-specific
CD4+ T cells of type 1 phenotype suggested that NK cells
are not a relevant source of early IFN- upon LCMV infection. This is
in agreement with the findings by Orange and Biron (37)
which indicated that it has not been possible to demonstrate IFN-
production on protein level by LCMV-induced NK cells (37)
although LCMV-induced NK cells express detectable levels of IFN-
mRNA (46). However, in vivo neutralization of IFN- in
IL-12-deficient mice resulted in induction of significant numbers of
LCMV-specific CD4+ T cells producing IL-4. This finding
suggests that IFN- produced after infection with LCMV is a crucial
cytokine for the Th cell phenotype commitment in the absence of IL-12.
This finding is in contrast to observations made in MHV-infected
IL-12-deficient mice where virus-induced type 1 cytokine patterns were
not reversed by in vivo neutralization of IFN- (31).
Thus in the case of LCMV infection it seems likely that the IFN-
present at early time points after infection is sufficient to control
the induction of a type 1 phenotype T cell response after a viral
infection. One possible source of IFN- during LCMV infection could
be activated LCMV-specific CD8+ T cells which have been
shown to produce IFN- (37, 45). However, it is
difficult to experimentally address the hypothesis that
IL-12-independent IFN- production by CD8+ T cells might
be involved in Th1 development in IL-12-deficient mice. Since depletion
of CD8+ T cells would interfere with virus clearance and
thus result in drastically elevated Ag levels, a comparison to normal
mice would be uninterpretable. Alternatively, other cytokines or host
factors could possibly compensate for the lack of endogenous IL-12 for
IFN- production. IFN-, characteristically induced upon most viral
infections, has been suggested to favor the development of type 1 Th
cells (47), although contrasting results have been
reported by Wenner et al. (48), who showed that IFN- is
unable to induce Th1 development in a TCR transgenic system. Moreover,
IFN-ß production has been shown to inhibit endogenous IL-12
synthesis and associated IFN- production
(49).
Mice deficient for IFN-regulatory factor 1 (IRF1) exhibit strongly
reduced Th1 responses (50); furthermore, the recently
described IFN--inducing factor is a strong IL-12-independent inducer
of IFN- and of Th1 development (51).
However, once virus-specific T cells are activated and start to
clonally expand, they are certainly an important source of IFN- by
themselves, which in turn may influence the phenotype of newly primed
virus-specific T cells. Interestingly, virus-specific type 1
CD4+ T cells seem to preserve their phenotype independently
of the presence of IL-12 in vivo, suggesting that the
IL-12-ß2-chain-mediated Th1 phenotype selection and phenotype
conservation might not be as crucial in vivo as it has been
demonstrated in vitro (52). It is unclear whether IFN-
can directly promote differentiation of Th1 cells. In vitro it has been
shown that in Con A-activated cultures cellular IFN- production was
enhanced in the presence of IFN- (53). Some in vivo
experiments provided strong evidence for a role of IFN- in
regulating priming for IFN--producing T cells. Treatment of mice
with anti-IFN- mAbs at the time of infection with
Leishmania major resulted in diminished production of
IFN- and increased IL-4 production when cells from draining lymph
nodes were restimulated in vitro (54, 55). However, other
experimental findings question the relevance of IFN- for the
development of Th1 responses (56).
In contrast to viral infections, IL-12 was shown to be important for
the control of infection with the intracellular bacterium L.
monocytogenes. Neutrophils, granulocytes, 
T cells, and
above all macrophages are important factors during the early phase of
the immune response, and the type 1 cytokines IFN- and TNF- are
essential for protection (38). Especially, IFN-
inhibits evasion of L. monocytogenes from the phagosome into
the cytoplasm (57). Apparently, L.
monocytogenes infection in IL-12-deficient mice did not seem to
adequately induce type 1 cytokine responses that could efficiently
activate macrophages to be as listeriocidal as in control mice at early
time points after infection. However, despite this reduced capability
of IL-12-deficient mice to initially control L.
monocytogenes infection, IL-12-deficient mice are able to clear
infection within 2 wk.
In conclusion, the in vivo relevance of IL-12 seems to depend on the nature of the infecting/immunizing agent: viruses seem to depend much less on the presence of IL-12 for the induction of (protective) type 1 T cell responses as compared to bacteria, parasites, and soluble protein Ags that seem to depend on more subtle T cell activation pathways involving the presence of IL-12.
|
|
|
|
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Annette Oxenius, Institute of Experimental Immunology, Schmelzbergstr. 12, 8091 Zürich, Switzerland. E-mail address:
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; VSV, vesicular stomatitis virus.
Received for publication June 17, 1998. Accepted for publication October 2, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production and type 1 cytokine responses. Immunity 4:471.[Medline]
synthesis and resistence during acute infection with Toxoplasma gondii. J. Immunol. 153:2533.[Abstract]
are costimulators of interferon production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc. Natl. Acad. Sci. USA 90:3725.-treated mice. J. Virol. 63:2813. production and antiviral defense. J. Immunol. 156:1138.[Abstract]
. J. Immunol. 139:1104.[Abstract]
and tumor necrosis factor . J. Exp. Med. 181:1615. production by T helper 1 cells. Eur. J. Immunol. 26:659.[Medline]
in monocytic cells. J. Exp. Med. 183:147.). Curr. Opin. Immunol. 9:17.[Medline]
ß, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. J. Immunol. 156:4746.[Abstract]
and IFN- in IL-12-induced T helper cell development. J. Immunol. 156:1442.[Abstract]
/ß inhibition of interleukin-12 and interferon- production in vivo and endogenously during viral infection. Proc. Natl. Acad. Sci. USA 94:634. production by T cells. Nature 378:88.[Medline]
direct the development of distinct subsets of helper T cells. Fed. Proc. 4:2020.
modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J. Immunol. 147:3149.[Abstract]
in CD4+ T cells. Int. Immunol. 5:877.-Interferon limits access of listeria monocytogenes to the macrophage cytoplasm. J. Exp. Med. 170:2141.This article has been cited by other articles:
|
|
 |
|
  Y. Y. Wan and R. A. Flavell How Diverse--CD4 Effector T Cells and their Functions J Mol Cell Biol, October 1, 2009; 1(1): 20 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Longhi, C. Trumpfheller, J. Idoyaga, M. Caskey, I. Matos, C. Kluger, A. M. Salazar, M. Colonna, and R. M. Steinman Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant J. Exp. Med., July 6, 2009; 206(7): 1589 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kapil, R. Atkinson, C. Ramakrishna, D. J. Cua, C. C. Bergmann, and S. A. Stohlman Interleukin-12 (IL-12), but Not IL-23, Deficiency Ameliorates Viral Encephalitis without Affecting Viral Control J. Virol., June 15, 2009; 83(12): 5978 - 5986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Liu, A. M. Woltman, H. L. A. Janssen, and A. Boonstra Modulation of dendritic cell function by persistent viruses J. Leukoc. Biol., February 1, 2009; 85(2): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ruan, L. McKinley, M. Zheng, X. Rudner, A. D'Souza, J. K. Kolls, and J. E. Shellito Interleukin-12 and Host Defense against Murine Pneumocystis Pneumonia Infect. Immun., May 1, 2008; 76(5): 2130 - 2137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. K. Case, L. Petell, L. Yurkovetskiy, A. Purdy, K. J. Savage, and T. V. Golovkina Replication of Beta- and Gammaretroviruses Is Restricted in I/LnJ Mice via the Same Genetic Mechanism J. Virol., February 1, 2008; 82(3): 1438 - 1447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Pearce and H. Shen Generation of CD8 T Cell Memory Is Regulated by IL-12 J. Immunol., August 15, 2007; 179(4): 2074 - 2081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Neff-LaFord, S. Teske, T. P. Bushnell, and B. P. Lawrence Aryl Hydrocarbon Receptor Activation during Influenza Virus Infection Unveils a Novel Pathway of IFN-{gamma} Production by Phagocytic Cells J. Immunol., July 1, 2007; 179(1): 247 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Johnson and P. Scott STAT1 Expression in Dendritic Cells, but Not T Cells, Is Required for Immunity to Leishmania major J. Immunol., June 1, 2007; 178(11): 7259 - 7266. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Liu, F. S. Machado, R. Guo, K. E. Nichols, A. W. Burks, J. C. Aliberti, and X.-P. Zhong Diacylglycerol kinase {zeta} regulates microbial recognition and host resistance to Toxoplasma gondii J. Exp. Med., April 16, 2007; 204(4): 781 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhou, E. A. Kurt-Jones, K. A. Fitzgerald, J. P. Wang, A. M. Cerny, M. Chan, and R. W. Finberg Role of MyD88 in Route-Dependent Susceptibility to Vesicular Stomatitis Virus Infection J. Immunol., April 15, 2007; 178(8): 5173 - 5181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Way, C. Havenar-Daughton, G. A. Kolumam, N. N. Orgun, and K. Murali-Krishna IL-12 and Type-I IFN Synergize for IFN-{gamma} Production by CD4 T Cells, Whereas Neither Are Required for IFN-{gamma} Production by CD8 T Cells after Listeria monocytogenes Infection J. Immunol., April 1, 2007; 178(7): 4498 - 4505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-R. Chang, K.-J. Wang, Y.-F. Lu, L.-J. Yang, W.-J. Chen, Y.-H. Lin, H.-H. Chang, and S.-L. Wang Characterization of Early Gamma Interferon (IFN-{gamma}) Expression during Murine Listeriosis: Identification of NK1.1+ CD11c+ Cells as the Primary IFN-{gamma}-Expressing Cells Infect. Immun., March 1, 2007; 75(3): 1167 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Nembrini, B. Abel, M. Kopf, and B. J. Marsland Strong TCR Signaling, TLR Ligands, and Cytokine Redundancies Ensure Robust Development of Type 1 Effector T Cells. J. Immunol., June 15, 2006; 176(12): 7180 - 7188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ato, A. Maroof, S. Zubairi, H. Nakano, T. Kakiuchi, and P. M. Kaye Loss of Dendritic Cell Migration and Impaired Resistance to Leishmania donovani Infection in Mice Deficient in CCL19 and CCL21 J. Immunol., May 1, 2006; 176(9): 5486 - 5493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Longhi, B. Sivasankar, N. Omidvar, B. P. Morgan, and A. Gallimore Cutting Edge: Murine CD59a Modulates Antiviral CD4+ T Cell Activity in a Complement-Independent Manner J. Immunol., December 1, 2005; 175(11): 7098 - 7102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wuthrich, T. Warner, and B. S. Klein IL-12 Is Required for Induction but Not Maintenance of Protective, Memory Responses to Blastomyces dermatitidis: Implications for Vaccine Development in Immune-Deficient Hosts J. Immunol., October 15, 2005; 175(8): 5288 - 5297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Berg, E. Crossley, S. Murray, and J. Forman Relative Contributions of NK and CD8 T Cells to IFN-{gamma} Mediated Innate Immune Protection against Listeria monocytogenes J. Immunol., August 1, 2005; 175(3): 1751 - 1757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Noone, E. A. Lewis, A. B. Frawely, R. W. Newman, B. P. Mahon, K. H. Mills, and P. A. Johnson Novel mechanism of immunosuppression by influenza virus haemagglutinin: selective suppression of interleukin 12 p35 transcription in murine bone marrow-derived dendritic cells J. Gen. Virol., July 1, 2005; 86(7): 1885 - 1890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Svensson, I. Nordstrom, J.-B. Sun, and K. Eriksson Protective Immunity to Genital Herpes Simpex Virus Type 2 Infection Is Mediated by T-bet J. Immunol., May 15, 2005; 174(10): 6266 - 6273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Lin, T. J. Roberts, P. M. Spence, and R. R. Brutkiewicz Reduction in CD1d expression on dendritic cells and macrophages by an acute virus infection J. Leukoc. Biol., February 1, 2005; 77(2): 151 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Klagge, M. Abt, B. Fries, and S. Schneider-Schaulies Impact of measles virus dendritic-cell infection on Th-cell polarization in vitro J. Gen. Virol., November 1, 2004; 85(11): 3239 - 3247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. N. Kristensen, A. N. Madsen, A. R. Thomsen, and J. P. Christensen Cytokine production by virus-specific CD8+ T cells varies with activation state and localization, but not with TCR avidity J. Gen. Virol., June 1, 2004; 85(6): 1703 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. de Wit, M. C. Horzinek, B. L. Haagmans, and V. E. J. C. Schijns Host-dependent type 1 cytokine responses driven by inactivated viruses may fail to default in the absence of IL-12 or IFN-{alpha}/{beta} J. Gen. Virol., April 1, 2004; 85(4): 795 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. X. Zhong, W. A. Kuziel, E. G. Pamer, and N. V. Serbina Chemokine Receptor 5 Is Dispensable for Innate and Adaptive Immune Responses to Listeria monocytogenes Infection Infect. Immun., February 1, 2004; 72(2): 1057 - 1064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Oleszak, J. R. Chang, H. Friedman, C. D. Katsetos, and C. D. Platsoucas Theiler's Virus Infection: a Model for Multiple Sclerosis Clin. Microbiol. Rev., January 1, 2004; 17(1): 174 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Elsawa and K. L. Bost Murine {gamma}-Herpesvirus-68-Induced IL-12 Contributes to the Control of Latent Viral Burden, but Also Contributes to Viral-Mediated Leukocytosis J. Immunol., January 1, 2004; 172(1): 516 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vollstedt, M. Franchini, H. P. Hefti, B. Odermatt, M. O'Keeffe, G. Alber, B. Glanzmann, M. Riesen, M. Ackermann, and M. Suter Flt3 Ligand-treated Neonatal Mice Have Increased Innate Immunity Against Intracellular Pathogens and Efficiently Control Virus Infections J. Exp. Med., March 3, 2003; 197(5): 575 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fieschi, S. Dupuis, E. Catherinot, J. Feinberg, J. Bustamante, A. Breiman, F. Altare, R. Baretto, F. Le Deist, S. Kayal, et al. Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor {beta}1 Deficiency: Medical and Immunological Implications J. Exp. Med., February 17, 2003; 197(4): 527 - 535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Smeltz, J. Chen, R. Ehrhardt, and E. M. Shevach Role of IFN-{gamma} in Th1 Differentiation: IFN-{gamma} Regulates IL-18R{alpha} Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor {beta}2 Expression J. Immunol., June 15, 2002; 168(12): 6165 - 6172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kanoh, T. Uetani, H. Sakan, S. Maruyama, F. Liu, K. Sumita, and Y. Asano A two-step model of T cell subset commitment: antigen-independent commitment of T cells before encountering nominal antigen during pathogenic infections Int. Immunol., June 1, 2002; 14(6): 567 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Y. Park, B. Hondowicz, M. Kopf, and P. Scott The Role of IL-12 in Maintaining Resistance to Leishmania major J. Immunol., June 1, 2002; 168(11): 5771 - 5777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Cote-Sierra, A. Bredan, C. M. Toldos, B. Stijlemans, L. Brys, P. Cornelis, M. Segovia, P. de Baetselier, and H. Revets Bacterial Lipoprotein-Based Vaccines Induce Tumor Necrosis Factor-Dependent Type 1 Protective Immunity against Leishmania major Infect. Immun., January 1, 2002; 70(1): 240 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Muller, G. Kohler, H. Mossmann, G. A. Schaub, G. Alber, J. P. Di Santo, F. Brombacher, and C. Holscher IL-12-Independent IFN-{gamma} Production by T Cells in Experimental Chagas' Disease Is Mediated by IL-18 J. Immunol., September 15, 2001; 167(6): 3346 - 3353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Neighbors, X. Xu, F. J. Barrat, S. R. Ruuls, T. Churakova, R. Debets, J. F. Bazan, R. A. Kastelein, J. S. Abrams, and A. O'Garra A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to Listeria monocytogenes That Extends Beyond Its Effects on Interferon {gamma} Production J. Exp. Med., August 6, 2001; 194(3): 343 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Del Rio, A. J. Buendia, J. Sanchez, M. C. Gallego, M. R. Caro, N. Ortega, J. Seva, F. J. Pallares, F. Cuello, and J. Salinas Endogenous Interleukin-12 Is Not Required for Resolution of Chlamydophila abortus (Chlamydia psittaci Serotype 1) Infection in Mice Infect. Immun., August 1, 2001; 69(8): 4808 - 4815. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Harandi, B. Svennerholm, J. Holmgren, and K. Eriksson Interleukin-12 (IL-12) and IL-18 Are Important in Innate Defense against Genital Herpes Simplex Virus Type 2 Infection in Mice but Are Not Required for the Development of Acquired Gamma Interferon-Mediated Protective Immunity J. Virol., July 15, 2001; 75(14): 6705 - 6709. [Abstract] [Full Text]
|
|
|
|
|
|
U. Dittmer, K. E. Peterson, R. Messer, I. M. Stromnes, B. Race, and K. J. Hasenkrug Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection J. Virol., January 15, 2001; 75(2): 654 - 660. [Abstract] [Full Text]
|
|
|
|
|
|
E. A. Patton, L. R. Brunet, A. C. La Flamme, J. Pedras-Vasconcelos, M. Kopf, and E. J. Pearce Severe Schistosomiasis in the Absence of Interleukin-4 (IL-4) Is IL-12 Independent Infect. Immun., January 1, 2001; 69(1): 589 - 592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cai, R. Kastelein, and C. A. Hunter Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii Infect. Immun., December 1, 2000; 68(12): 6932 - 6938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Cai, T. Radzanowski, E. N. Villegas, R. Kastelein, and C. A. Hunter Identification of STAT4-Dependent and Independent Mechanisms of Resistance to Toxoplasma gondii J. Immunol., September 1, 2000; 165(5): 2619 - 2627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Subauste and M. Wessendarp Human Dendritic Cells Discriminate Between Viable and Killed Toxoplasma gondii Tachyzoites: Dendritic Cell Activation After Infection with Viable Parasites Results in CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and -Independent T Cell Production of IFN-{gamma} J. Immunol., August 1, 2000; 165(3): 1498 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Maloy, C. Burkhart, T. M. Junt, B. Odermatt, A. Oxenius, L. Piali, R. M. Zinkernagel, and H. Hengartner Cd4+ T Cell Subsets during Virus Infection: Protective Capacity Depends on Effector Cytokine Secretion and on Migratory Capability J. Exp. Med., June 19, 2000; 191(12): 2159 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Rottenberg, A. Gigliotti Rothfuchs, D. Gigliotti, M. Ceausu, C. Une, V. Levitsky, and H. Wigzell Regulation and Role of IFN-{gamma} in the Innate Resistance to Infection with Chlamydia pneumoniae J. Immunol., May 1, 2000; 164(9): 4812 - 4818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xing, A. Zganiacz, J. Wang, M. Divangahi, and F. Nawaz IL-12-Independent Th1-Type Immune Responses to Respiratory Viral Infection: Requirement of IL-18 for IFN-{gamma} Release in the Lung But Not for the Differentiation of Viral-Reactive Th1-Type Lymphocytes J. Immunol., March 1, 2000; 164(5): 2575 - 2584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ashkar, G. F. Weber, V. Panoutsakopoulou, M. E. Sanchirico, M. Jansson, S. Zawaideh, S. R. Rittling, D. T. Denhardt, M. J. Glimcher, and H. Cantor Eta-1 (Osteopontin): An Early Component of Type-1 (Cell-Mediated) Immunity Science, February 4, 2000; 287(5454): 860 - 864. [Abstract] [Full Text]
|
|
|
|
|
|
M. van den Broek, M. F. Bachmann, G. Kohler, M. Barner, R. Escher, R. Zinkernagel, and M. Kopf IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-{gamma} and Nitric Oxide Synthetase 2 J. Immunol., January 1, 2000; 164(1): 371 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Simmons, P. Mastroeni, R. Fowler, M. Ghaem-maghami, N. Lycke, M. Pizza, R. Rappuoli, and G. Dougan MHC Class I-Restricted Cytotoxic Lymphocyte Responses Induced by Enterotoxin-Based Mucosal Adjuvants J. Immunol., December 15, 1999; 163(12): 6502 - 6510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Holz, A. Bot, B. Coon, T. Wolfe, M. J. Grusby, and M. G. von Herrath Disruption of the STAT4 Signaling Pathway Protects from Autoimmune Diabetes While Retaining Antiviral Immune Competence J. Immunol., November 15, 1999; 163(10): 5374 - 5382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Stobie, S. Gurunathan, C. Prussin, D. L. Sacks, N. Glaichenhaus, C.-Y. Wu, and R. A. Seder The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge PNAS, July 18, 2000; 97(15): 8427 - 8432. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
