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-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking1
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Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; and
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducible protein 10 (IP-10, CXCL10), a chemokine secreted
from cells stimulated with type I and II IFNs and LPS, is a
chemoattractant for activated T cells. Expression of IP-10 is seen in
many Th1-type inflammatory diseases, where it is thought to play an
important role in recruiting activated T cells into sites of tissue
inflammation. To determine the in vivo function of IP-10, we
constructed an IP-10-deficient mouse (IP-10-/-) by
targeted gene disruption. Immunological analysis revealed that
IP-10-/- mice had impaired T cell responses. T cell
proliferation to allogeneic and antigenic stimulation and IFN-
secretion in response to antigenic challenge were impaired in
IP-10-/- mice. In addition, IP-10-/- mice
exhibited an impaired contact hypersensitivity response, characterized
by decreased ear swelling and reduced inflammatory cell infiltrates. T
cells recovered from draining lymph nodes also had a decreased
proliferative response to Ag restimulation. Furthermore,
IP-10-/- mice infected with a neurotropic mouse hepatitis
virus had an impaired ability to control viral replication in the
brain. This was associated with decreased recruitment of
CD4+ and CD8+ lymphocytes into the brain,
reduced levels of IFN- and the IFN--induced chemokines monokine
induced by IFN- (Mig, CXCL9) and IFN-inducible T cell 
chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of
virus-specific IFN--secreting CD8+ cells in the spleen,
and reduced levels of demyelination in the CNS. Taken together, our
data suggest a role for IP-10 in both effector T cell generation and
trafficking in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducible protein of 10 kDa
(IP-10/CXCL10)5 as an early
response gene induced by IFN- in U937 cells (a monocyte-like cell
line) (1). IP-10 is constitutively expressed at low levels
in thymic, splenic, and lymph node stroma (2). However,
expression can be highly induced in a variety of cells, including
endothelial cells, keratinocytes, fibroblasts, mesangial cells,
astrocytes, monocytes, and neutrophils by stimulation with IFN-,
IFN-
, IFN-, or LPS and in T cells by Ag activation
(3, 4, 5). IP-10 is also expressed in many Th1-type human
inflammatory diseases, including skin diseases (e.g., psoriasis)
(6, 7), multiple sclerosis (8, 9),
atherosclerosis (10), rheumatoid arthritis
(11), transplant rejection (12, 13), and
inflammatory bowel diseases (14). Elevated levels of IP-10
protein have been found in the cerebral spinal fluid in patients with
viral meningitis (15) and multiple sclerosis
(8), in the bronchoalveolar lavage fluid of patients with
pulmonary sarcoidosis (16) and lung transplantation
undergoing rejection (13), and in the serum of patients
with chronic active hepatitis (17). In these diseases,
levels of IP-10 correlate with the tissue infiltration of T
lymphocytes, suggesting that IP-10 plays an important role in the
recruitment of T cells to sites of inflammation.
IP-10 is structurally and functionally related to monokine induced by
IFN- (Mig, CXCL9) and IFN-inducible T cell chemoattractant
(I-TAC, CXCL11). These three chemokines direct migration and stimulate
the adhesion of activated T cells and NK cells by binding to and
activating CXCR3, a G protein-coupled receptor. CXCR3 is expressed on
activated T cells, preferentially of the Th1 phenotype, on NK cells,
and on a significant fraction of circulating CD4+
and CD8+ T cells (
20–40%)
(18, 19, 20). The majority of peripheral
CXCR3+ T cells express CD45RO (memory T cells) as
well as 1 integrins (20), which
are implicated in the binding of lymphocytes to endothelial cells and
the extracellular matrix (21). In addition, CXCR3 has been
reported to be expressed on plasmacytoid and myeloid dendritic cells
(22, 23), leukemic B cells (24, 25),
eosinophils (26), dividing microvascular endothelial cells
(27, 28), thymocyte subsets (29), and
GM-CSF-treated CD34+ cord blood cells
(30).
Among the CXC chemokines, IP-10, Mig, and I-TAC are unique in that they
are all induced by IFN- in a wide variety of cell types (3, 10, 31, 32) and act through the chemokine receptor CXCR3.
However, while these three ligands activate the same receptor, it is
becoming clear that they exhibit unique expression patterns in
vivo, and experiments using neutralizing Abs and gene-targeted mice
support the concept that these three chemokines may have nonredundant
functions in vivo. Compared with Mig and I-TAC, IP-10 expression is
seen earlier following infection with a variety of pathogens and in
response to LPS injection (33, 34, 35). In addition,
differential expression of IP-10, Mig, and I-TAC has been demonstrated
in human atherosclerotic lesions in situ (10) and in
several skin diseases, including psoriasis (7, 36). mAb
neutralization demonstrated that IP-10 is required for survival
following infection of mice with Toxoplasma gondii
(34) and cannot be substituted by other CXCR3 chemokine
ligands. Neutralization of IP-10 inhibited T cell infiltration into
infected tissues and impaired Ag-specific T cell effector functions,
resulting in a massive increase in tissue parasite burden, leading to
increased mortality. Ab neutralization of IP-10 has also been shown to
block the recruitment of effector T cells into the CNS in a passive
transfer model of murine experimental autoimmune encephalomyelitis
(37). In addition, in a murine viral hepatitis model with
both acute and chronic stages of CNS inflammation and injury,
neutralization of IP-10 increased mortality and delayed viral clearance
from the CNS in the acute phase (38). This was associated
with reduced effector T cell recruitment into the brain. In addition,
in the chronic phase anti-IP-10 treatment inhibited progression of
demyelination, increased remyelination, and improved neurological
function (39). Interestingly, anti-Mig treatment had
no effect on the chronic phase of the illness, confirming that IP-10
and Mig can subserve different biological functions in vivo. This has
also been suggested by studies that revealed that Ab neutralization of
Mig inhibited T cell infiltration into class II MHC-disparate murine
skin allografts and inhibited acute rejection (40). This
concept is further supported by our recent studies using the
IP-10-deficient mice that we describe here, which demonstrated a
requirement for allograft-derived IP-10 for the early recruitment of NK
cells and T cells into cardiac allografts to initiate acute rejection
(41).
In addition to their well-described function of recruiting leukocytes
to sites of inflammation, chemokines also play a role in the generation
and function of effector cells. In fact, IP-10 has been shown to
augment IFN- release from PBMC cultures following stimulation with
environmental Ags (42). Furthermore, mAb neutralization
has also revealed a role for IP-10 in the generation of tumor-specific
effector T cells and tumor protective immunity in an IL-12 gene therapy
model (43). These data suggest that IP-10 and CXCR3 may
play a role in the generation and function of effector T cells, in
addition to or as a result of their activity in T cell recruitment.
In this study mice deficient in IP-10 were generated and found to have an impaired response to alloantigen stimulation in MLR assays and reduced T cell responses following primary immunization with exogenous Ag. These mice also exhibited a reduced contact hypersensitivity response and an impaired host immune response to mouse hepatitis virus (MHV) infection that was characterized by decreased generation and tissue recruitment of effector T cells. These data demonstrate that IP-10 plays a role in the generation and delivery of an effector T cell response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A mouse 129Sv/J genomic library (Stratagene, La Jolla, CA) was
screened with a mouse IP-10 cDNA probe (4, 5) to isolate a
phage, p
26, which contained 20 kb of IP-10 genomic DNA. To
disrupt the IP-10 gene, a 5.5-kb XbaI (X)-EcoRV
(RV) fragment that includes only exon 4 was subcloned into PGK-Neo,
which contains the gene for neomycin resistance driven by the
phosphoglycerate kinase promoter (see Fig. 1
). A 2-kb PCR product
containing sequences upstream of the IP-10-coding region was generated
using murine chromosomal DNA and primers based on the published murine
IP-10 gene sequence (44). The upstream primer included a
SalI (S) restriction site, and the downstream primer
included a XhoI (Xh) site. These sites were used to subclone
the PCR product into the unique SalI site of the targeting
vector. To provide negative selection for a single homologous
recombination event, the gene for thymidine kinase, driven by the HSV
promoter, was cloned into the targeting vector. The IP-10 targeting
vector was used to electroporate J1 embryonic stem (ES) cells and
selected for neomycin resistance.
1-(2-Deoxy-2-fluoro-1--D-arabino-furanosyl)-5-iodouracil
was added, and the resulting clones were picked on day 7
postelectroporation. The frequency of homologous recombination in ES
cells was 0.5%. An ES clone containing the disrupted allele was
injected into blastocysts and resulted in live births after transfer to
a foster mother. The chimeras from this clone passed the disrupted
allele to their progeny, which were intercrossed to produce mice
homozygous for the disrupted allele. Mice were genotyped by Southern
blot analysis of DNA digested with XbaI using standard
techniques. Using an 500 bp genomic DNA fragment upstream from the
XhoI site at the 5' end of exon 1 as a probe, the wild-type
allele generated a 2-kb hybridizing fragment; the disrupted allele
generated a larger 2.7-kb fragment. Additional confirmatory Southern
blots of ES clones were performed using the neomycin resistance gene as
a probe on BamHI-digested DNA and an IP-10 cDNA probe on
XbaI- or SacI-digested DNA. The initial chimeric
mice (129Sv/J ES cell into C57BL/6 blastocyst) were mated back to
129Sv/J mice to introduce the disrupted allele onto a pure 129Sv/J
background. IP-10+/+ and
IP-10-/- mice on a pure 129Sv/J background were
used in all experiments, with the exception of the MHV model. For the
MHV experiments, (129Sv/J x C57BL/6)F1
IP-10-/- and IP-10+/+
littermate control mice were used. All mice were used between 6–12 wk
of age.
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Briefly, bone marrow was flushed from the femurs of mice and
cultured for 7 days in the presence of 5 ng/ml M-CSF (PeproTech, Rocky
Hill, NJ) in DMEM supplemented with 10% FCS, 2 mM
L-glutamine, 100 µg/ml streptomycin, 100 U/ml penicillin,
1 mM sodium pyruvate, and 50 µM -ME (CD10; Cellgro-Mediatech,
Herndon, VA). Bone marrow-derived macrophages were then stimulated with
100 ng/ml IFN- or 100 ng/ml LPS in the presence of serum for 5
h, and RNA was isolated using RNA STAT-60 (Tel-Test, Friendswood, TX).
RNA was fractionated on a 1.2% agarose gel containing 0.7%
formaldehyde, transferred to GeneScreen (DuPont-NEN, Boston, MA)
overnight using 10x SSC, and fixed to the membrane by UV cross-linking
(Stratalinker; Stratagene). The membrane was hybridized with
[32P]dCTP Klenow-labeled random primed murine
cDNA probes for IP-10, Mig (provided by Dr. J. Farber), I-TAC
(provided by Dr. G. Werner-Felmayer), KC, and actin as a control
for RNA loading. The membrane was hybridized under high stringency
conditions (50% formamide, 10% dextran sulfate, 5x SSC, 1x
Denhardt’s solution, 1% SDS, 100 µg/ml denatured herring sperm DNA,
and 20 mM Tris at 42°C) and washed at 55°C in 0.2x SSC and
0.1% SDS.
Western blot analysis
Bone marrow-derived macrophages were stimulated with 100 ng/ml
IFN- or 100 ng/ml LPS in the presence of serum for 5 h.
Macrophages were washed, and stimulants were added in serum-free medium
for an additional 48 h. Culture supernatants were collected,
clarified by centrifugation, and concentrated using Centricon-3
concentration units (Amicon, Beverly, MA). Samples were resolved on a
12.5% Tris-tricine acrylamide gel and transferred to polyvinylidene
difluoride membrane (DuPont-NEN). IP-10 secretion was determined by
immunoblotting with rabbit polyclonal antiserum to IP-10
(45) and detection by chemiluminescence (DuPont-NEN).
Recombinant murine IP-10 (PeproTech) was used as a control.
Mixed lymphocyte reactions
Responding splenocytes (IP-10+/+ or IP-10-/- 129Sv/J, H-2b or BALB/c, H-2d) were cultured with 2 x 105 mitomycin C (Sigma-Aldrich, St. Louis, MO)-treated syngeneic or allogeneic splenocytes or Con A (10 µg/ml; Calbiochem, La Jolla, CA) for 6 days at 37oC in a 5% CO2 atmosphere. Proliferation was determined by incorporation of [methyl-3H]thymidine (DuPont-NEN) during the final 18 h of culture.
Response to OVA
Mice were immunized with 100 µg OVA (Sigma-Aldrich) in CFA
(Sigma-Aldrich) i.p. Seven days later animals were sacrificed, and
serum Ig isotypes were determined using an OVA-specific ELISA (Pierce,
Rockford, IL). A series of serum dilutions was examined in each
experiment, and dilutions (1/100) in the linear range of the assay were
reported. Lymph nodes were aseptically removed on day 7 postinfection
(p.i.), dispersed into single-cell suspensions, and stimulated in the
presence or the absence of 50 µg/ml OVA in vitro for 48 h.
Proliferation was determined by incorporation of
[3H]thymidine. Culture supernatants were
collected at 48 h from duplicate cultures and were assayed by
ELISA for IFN-, IL-4, and IL-5 (Endogen, Woburn, MA).
Contact hypersensitivity response
Mice were sensitized by application of 0.05 ml 0.5% 2,4-dinitro-1-fluorobenzene (DNFB; Sigma-Aldrich) (dissolved in 3/1 acetone/olive oil) to the shaved backs of animals. Six days later, the baseline thickness of the animal’s ears was measured using a precision thickness gauge (Mitutoyo, Aurora, IL). Each side of the ear was then treated epicutaneously with 0.01 ml of 0.2% DNFB in acetone, and ear thickness was measured 24 h later. Ear swelling was determined by subtracting prechallenge ear thickness from measurements 24 h postchallenge. For histopathologic analysis, ears were fixed in 10% neutral buffered formalin. Tissues were embedded in paraffin, sectioned, and stained with H&E. For proliferation assays, cervical lymph nodes were removed 24 h postchallenge and dispersed into single-cell suspensions. Cells (2 x 105) were stimulated in vitro in the absence or the presence of 50 µg/ml dinitrobenzene sulfonate (DNBS, soluble analog of DNFB; Sigma-Aldrich) for 48 h. Proliferation was determined by incorporation of [3H]thymidine.
Infection with MHV
IP-10+/+ and
IP-10-/- mice were injected intracranially
(i.c.) with 1000 PFU MHV strain J2.2V-1 suspended in 30 µl sterile
saline. Control animals received an i.c. injection of saline alone. To
determine viral burden following infection,
IP-10-/- and IP-10+/+
mice were sacrificed on days 7 and 12 p.i. Brains were removed,
and one-half was used for plaque assay on the DBT astrocytoma cell line
as previously described (46). The remaining halves of
brain were used for immunophenotyping the cellular infiltrate by flow
cytometry using a previously published protocol (46).
FITC-conjugated Abs to CD4 and CD8 (BD PharMingen, San Diego, CA) were
used to detect infiltrating T lymphocytes. FITC-conjugated F4/80
(Serotec, Oxford, U.K.) was used to detect activated
macrophages/microglial cells. For RT-PCR analysis, total RNA was
extracted from brains of mice at 7 days p.i. using TRIzol reagent (Life
Technologies, Gaithersburg, MD) and were reverse transcribed using the
AMV reverse transcriptase system (Promega, Madison, WI). PCR
amplification was performed on the resulting cDNA for 30 cycles with
specific primers for L32 (forward, 5'-AACGCTCAGCTCCTTGACAT; reverse,
5'-AACCCAGAGGCATTGACAAC), Mig (forward, 5'-CGTCGTCGTTCAAGGAAG;
reverse, 5'-TCGAAAGCTTGGGAGGTT), I-TAC (forward,
5'-GCGGCCGCGAGGACGCTGTCTTTGCATAGG; reverse,
5'-GAATTCAGCCTTGCTTGCTTCGATTTGG), or IFN- (Clontech
Laboratories, South San Francisco, CA). Sequence analysis of L32, Mig,
and I-TAC amplicons confirmed primer specificity. Amplification was
performed on an automated PerkinElmer/Cetus (Norwalk, CT) model 480 DNA
thermocycler using the following profile: step 1, initial denaturation
at 94°C for 45 s; step 2, annealing at 60°C for 45 s; and
step 3, extension at 72°C for 2 min. Steps 1–3 were repeated 29
times for a total of 30 cycles and were followed by a 7-min incubation
at 72°C.
LFB staining of spinal cords and analysis by light microscopy
Demyelination was scored on spinal cords stained with Luxol fast blue (LFB). Demyelination was scored as follows: 0, no demyelination; 1, mild inflammation accompanied by loss of myelin integrity; 2 moderate inflammation with increasing myelin damage; 3, numerous inflammatory lesions accompanied by significant increase in myelin stripping; and 4, intense areas of inflammation accompanied by numerous phagocytic cells engulfing myelin debris (46). Scores were averaged and are presented as the average ± SEM.
Intracellular cytokine staining
Intracellular cytokine staining was performed using a previously
described procedure (47). In brief,
IP-10+/- and IP-10-/-
mice were infected i.p. with 2 x 105 PFU
MHV-4. Splenocytes were isolated at 8 days p.i. and pooled, and 1
x 106 total cells were stimulated with peptide
corresponding to the CD8 epitope in the surface (S) glycoprotein
spanning residues 510–518 (S510–518) (48, 49). After
incubation for 6 h at 37°C in medium containing Golgi stop
(Cytofix/Cytoperm kit; BD PharMingen), cells were washed, and blocked
with PBS containing 10% FBS and a 1/200 dilution of CD16/32 (BD
PharMingen). Cells were then stained for surface Ags with either
FITC-conjugated CD8 or rat IgG2b (as control) for 45 min at 4°C and
stained for intracellular IFN- using PE-conjugated anti-IFN-
(1/50; XMG1.2; BD PharMingen) for 45 min at 4°C. Cells were analyzed
on a FACStar (BD Biosciences, Mountain View, CA). Data are presented as
the percentage of positive cells within the gated population. The
absolute numbers of activated CD8+ T lymphocytes
was calculated by multiplying the fraction of dual-positive cells by
the total number of cells obtained from the spleen.
Statistical analysis
Data were analyzed by Student’s t test (two-tailed, paired). A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice deficient in IP-10 were generated by targeted gene deletion
mutagenesis (Fig. 1
). A targeting vector
(Fig. 1A) was designed that would delete exons 1–3,
virtually the entire coding region of IP-10. The targeting vector was
electroporated into J1 ES cells and selected for neomycin resistance.
An ES clone containing the disrupted allele was injected into
blastocysts and resulted in live births after transfer to a foster
mother. The chimeras from this clone passed the disrupted allele to
their progeny, which were intercrossed to produce mice homozygous for
the disrupted allele. Mice were genotyped by Southern blot analysis
using a genomic DNA fragment 5' of exon 1 as a probe (Fig. 1B). The wild-type allele generated a 2-kb hybridizing
fragment, and the disrupted allele generated a larger 2.7-kb
fragment.
To confirm that IP-10 expression had been disrupted, Northern blot
analysis was performed (Fig. 1C).
IP-10-/- mice expressed no detectable mRNA for
IP-10 following IFN- or LPS stimulation compared with prominent
IP-10 mRNA expression in wild-type (IP-10+/+) and
heterozygous (IP-10+/-) mice. The expression of
other CXC chemokine genes that cluster with IP-10 on murine chromosome
5, such as Mig, I-TAC, and KC was not affected in
IP-10-/- mice (Fig. 1C). IP-10
protein secretion was measured in IFN-- or LPS-activated bone
marrow-derived macrophage cultures by immunoblotting culture
supernatants with an affinity-purified rabbit polyclonal anti-serum
to IP-10 (Fig. 1D). This analysis demonstrated the absence
of IP-10 secretion by macrophages derived from
IP-10-/- compared with
IP-10+/+ and IP-10+/-
mice.
IP-10-/- mice were born at the expected Mendelian ratios, showed no overt developmental or morphological abnormalities, and were fertile. Immunophenotyping of leukocyte subsets by flow cytometry from spleen, lymph node, thymus, bone marrow, and peripheral blood of IP-10-/- mice using mAbs directed against the neutrophil marker GR-1, the macrophage marker F4/80, the B cell marker B-220, and the T cell markers CD3, CD4, CD8, and CD25 were similar between wild-type and IP-10-/- mice (at least three animals tested for each genotype for each site in three separate experiments; data not shown).
Decreased responses to alloantigen in IP-10-/- mice
The MLR is a model of T cell responsiveness to allogeneic MHC Ags
and has been used to investigate the pathways of T cell proliferation.
Additionally, the MLR response potentially reflects the activation
pathway in acute allograft rejection. We analyzed the generation of an
allospecific proliferative response using naive
IP-10-/- and IP-10+/+
(H-2b) and BALB/c splenocytes
(H-2d) as both stimulators and responders.
Splenocytes from IP-10-/- mice exhibited a
significantly reduced proliferative response compared with
IP-10+/+ responses (68% reduced;
p = 0.021; Fig. 2A), while the proliferative
response to the mitogen Con A was unaffected. In contrast, splenocytes
from IP-10-/- and
IP-10+/+ mice stimulated comparable allogeneic
responses by BALB/c responder splenocytes (Fig. 2B). These
data demonstrate that IP-10-/- T cells exhibit
an impaired proliferative response to allogeneic stimulation.
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secretion to exogenous Ag in
IP-10-/- mice
To examine the role of IP-10 in T cell priming, we analyzed the
immune response of IP-10+/+ and
IP-10-/- mice following primary immunization
with a model Ag. IP-10+/+ and
IP-10-/- mice were immunized with 100 µg OVA
in CFA. Seven days later, mesenteric lymph nodes were harvested, and
cells were restimulated in vitro with OVA for 48 h. The
Ag-specific proliferative response of IP-10-/-
mice was significantly reduced (65% reduced; p =
0.027; Fig. 3A) compared with
that of IP-10+/+ mice. Another characteristic of
T cell activation is cytokine production following Ag stimulation.
Secretion of IFN-, a potent Th1-type cytokine, was reduced by
60% in OVA-stimulated IP-10-/- lymphocyte
cultures compared with IP-10+/+ cultures
(p = 0.021; Fig. 3B). Levels of IL-4
were not detectable by ELISA in either group, and levels of IL-5 were
not significantly different (data not shown). To ensure that the
differences we observed were not the result of a difference in the
kinetics of T cell activation in IP-10-/- mice,
we immunized IP-10-/- and
IP-10+/+ mice with OVA, harvested mesenteric
lymph nodes on days 3, 7, 10, and 14 days postimmunization, and
measured proliferation and IFN- secretion after in vitro
restimulation with OVA. IP-10-/- mice exhibited
the same kinetics of Ag-induced proliferation and peak IFN-
secretion as IP-10+/+ mice, although at lower
levels (data not shown).
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has been demonstrated to induce Ig heavy chain class switching
to IgG2a, while it inhibits class switching to IgG1 and IgE induced by
IL-4 (50). Because IFN- secretion in response to Ag
stimulation was impaired in IP-10-/- mice, we
examined the levels of serum IgG2a, IgG2b, and IgG1 on day 7 post-OVA
immunization using an OVA-specific Ig isotype ELISA. The levels of
OVA-specific IgG2a were significantly reduced (56% reduced;
p < 0.027; Fig. 3C) in serum from
IP-10-/- mice compared with that from
IP-10+/+ mice. IP-10-/- mice exhibit a reduced contact hypersensitivity response
To elucidate the role of IP-10 in the development of a
Th1-mediated immune response in vivo where IP-10 has been shown to be
up-regulated, we used an experimental model of contact hypersensitivity
(51). Results from several studies support a role for both
CD4+ and CD8+ T cells and
IFN- as the effectors of this response (52, 53). During
the contact hypersensitivity response, chemokines, including IP-10 and
monocyte chemoattractant protein-1 (MCP-1, CCL2), are expressed and
thought to mediate the influx of leukocytes into the skin (51, 54, 55). Mice were sensitized with DNFB and 7 days later were
challenged by hapten application on the inner and outer skin of the
ear. IP-10-/- mice exhibited a small (28%),
yet statistically significant, reduction in ear swelling compared with
IP-10+/+ mice (p = 0.01;
Fig. 4). Unsensitized
IP-10-/- and IP-10+/+
mice challenged with DNFB in acetone demonstrated a comparable modest
increase in ear swelling, indicating that IP-10 does not play a role in
the acute irritant response (data not shown). Histopathologic analysis
of ear tissue revealed significant edema and inflammatory leukocyte
infiltrates in IP-10+/+ mice, which were reduced
in ear tissue from IP-10-/- mice (Fig. 4A). To more directly determine the effects of IP-10
depletion on T cell function in this model, lymphocytes from draining
cervical lymph nodes excised at 24 h postchallenge were stimulated
in vitro with DNBS, a water-soluble analog of DNFB. Ag-specific
proliferation was reduced by 54% in
IP-10-/- mice compared with
IP-10+/+ mice (p = 0.032;
Fig. 4C). This decrease in Ag-induced proliferation of
lymphocytes may be the result of fewer Ag-specific T cells recruited
into the draining lymph nodes, an impaired T cell proliferative
response in IP-10-/- mice, or a combination
of both.
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We also examined the role of IP-10 in the host response to
a viral pathogen that requires T cell-mediated, organ-specific
immunity. Previous studies have shown that IP-10 is expressed by
astrocytes during acute encephalomyelitis in mice infected with the
neurotropic coronavirus MHV, and the majority of T lymphocytes that
infiltrate the CNS express CXCR3 (38). To determine the
role of IP-10 in viral clearance from the CNS, both
IP-10+/+ and IP-10-/-
mice were infected with MHV, and viral titers were examined at 7 and 12
days p.i. At 7 days p.i., both IP-10+/+ and
IP-10-/- mice showed comparable levels of
virus. However, by day 12 p.i., IP-10-/-
mice displayed significantly higher titers of virus (3.13 ± 0.21
log10 PFU/g) compared with
IP-10+/+ mice, which cleared virus below the
levels of assay sensitivity (<2 log10 PFU/g;
p < 0.001; Fig. 5A).
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78 and
75% decreases, respectively; p < 0.01) as
well as a significant decrease in macrophage infiltration (43%
decrease; p < 0.05) compared with
IP-10+/+ mice at day 7 p.i. (Fig. 5A). By day 12 both CD4+ and
CD8+ T cell numbers remained significantly lower
in brains of IP-10-/- mice compared with
IP-10+/+ mice. Macrophage numbers on day 12 were
reduced in IP-10-/- mice compared with
wild-type mice, although not significantly.
One mechanism by which T cells contribute to host defense against MHV
infection of the CNS is through the release of IFN-
(56). To determine whether IFN- levels were altered in
MHV-infected IP-10-/- mice, cytokine transcript
levels within the CNS of IP-10-/- and
IP-10+/+ mice were evaluated by RT-PCR on day
7 p.i. IP-10-/- mice display a marked
decrease in IFN- expression compared with
IP-10+/+ mice (Fig. 5B).
The decrease in T lymphocyte infiltration following CNS viral infection
of IP-10-/- mice suggested that other
chemokines were not adequately compensating for the loss of IP-10
activity. Mig and I-TAC are the two additional CXCR3 chemokine agonists
described and are also potent chemoattractants for activated T
lymphocytes. However, unlike IP-10, which is inducible by both
IFN- as well as IFN-, Mig expression is more dependent on
IFN- (1, 57). The decrease in CNS IFN- expression
suggested that the expression of Mig and I-TAC may also be affected in
MHV-infected IP-10-/- mice. Examination of Mig
and I-TAC transcripts at 7 days p.i. using RT-PCR showed a marked
decrease in the level of CNS Mig and I-TAC mRNA in
IP-10-/- mice compared with
IP-10+/+ mice (Fig. 5B). These data
suggest that in the absence of IP-10, Th1 cells are not effectively
recruited into the brain, resulting in decreased IFN- production and
therefore decreased Mig and I-TAC expression.
Decreased numbers of effector CD8 T lymphocytes in the spleen following MHV infection of IP-10-/- mice
The absence of IP-10 activity resulted in inhibition of a
protective Th1 response characterized by decreased numbers of
infiltrating T cells and IFN- expression in the brain. To determine
whether IP-10 plays a role in the generation of MHV-specific effector T
cells, the CD8+ T cell response to virus in
MHV-infected IP-10+/+ and
IP-10-/- mice was evaluated. Mice from both
groups received an i.p. injection of MHV (2 x
105 PFU), spleens were removed at day 8
postinjection, and a single-cell suspension was obtained. The
immunodominant epitope of MHV recognized by CD8+
T cells is found on the surface glycoprotein at residues 510–518
(S510–518) (48, 49). Isolated splenocytes from
IP-10+/+ and IP-10-/-
mice were stimulated with the CD8 viral epitope (S510–518) and dual
stained for CD8 and IFN-. The total numbers of cells found within
the spleens of IP-10+/+ and
IP-10-/- mice were comparable. However, the
total number of CD8+ T cells within the spleens
of IP-10-/- mice was decreased by 25%
compared with that in IP-10+/+ mice
(IP-10-/-, 4.5 x
106 cells; IP-10+/+, 6
x 106 cells). In addition,
IP-10-/- mice had a decrease (40%) in the
percentage of CD8+ T lymphocytes responding to
viral peptide S510–518 compared with IP-10+/+
mice (Fig. 6A). Furthermore,
such analysis revealed an 2-fold decrease in total numbers of
activated CD8+ T lymphocytes present within the
spleen of immunized IP-10-/- mice compared with
IP-10+/+ (Fig. 6B). Collectively,
these data suggest that the generation and/or effector activity of
CD8+ T lymphocytes were affected by the absence
of IP-10 activity.
|
Effector T lymphocytes and macrophages are important in driving
MHV-induced demyelination (46). Further, a recent study by
Liu et al. (39) showed that Ab-mediated neutralization of
IP-10 during established MHV-induced demyelination resulted in
diminished clinical and histological disease that correlated with
decreased CD4+ T cell and macrophage infiltration
within the CNS. Taken together, these data suggest that demyelination
may be altered within the CNS of IP-10-/- mice.
To address this possibility, demyelination was assessed within
LFB-stained spinal cords taken from IP-10-/-
and IP-10+/+ mice infected with MHV at 12 days
p.i. As shown in Fig. 7, mice lacking
IP-10 displayed significantly reduced (p <
0.005) levels of demyelination compared with wild-type mice, supporting
Ab neutralization studies that indicated a prominent role for this
chemokine in contributing to MHV-induced demyelination.
|
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion, supporting a role for IP-10 in T cell priming in vivo.
IP-10-/- mice also exhibited an impaired
contact hypersensitivity response, characterized by decreased ear
swelling and reduced inflammatory cell infiltrates. In addition,
lymphocytes from draining lymph nodes of sensitized and challenged
IP-10-/- mice had a decreased proliferative
response to Ag restimulation in vitro. Lastly,
IP-10-/- mice infected with a neurotropic MHV
had an impaired ability to control viral replication in the brain. This
was associated with decreased recruitment of CD4+
and CD8+ lymphocytes into the brain; reduced
levels of IFN-, Mig, and I-TAC in the brain; and impaired generation
of viral-specific CD8+ T cells. Thus, IP-10
appears to play a role in both the generation of effector T cells and
their delivery to sites of tissue inflammation. Increasing data support the concept that IP-10 plays an important role in attracting effector T cells into sites of Th1-type inflammation. IP-10 is highly expressed in the tissue in Th1 inflammation, and CXCR3+ T cells are found to be highly enriched juxtaposed to IP-10 at these inflammatory sites. Our study demonstrated that IP-10-/- mice have decreased inflammatory cell recruitment into the skin in a contact hypersensitivity response and decreased effector T cell recruitment into the CNS in a murine model of MHV infection resulting in reduced demyelination These data are consistent with Ab neutralization studies, which have revealed a role for IP-10 in effector T cell trafficking into organs infected with the intracellular parasite T. gondii (34) and into the CNS in a murine model of EAE (37) and MHV infection (38). Furthermore, recent studies with the IP-10-/- mice we describe here and with CXCR3-/- mice demonstrated a role for donor-derived IP-10 and host-derived CXCR3 in the recruitment of NK cells and effector T cells into murine cardiac allografts delaying rejection (41, 58). Thus, data from Ab neutralization studies and gene-targeted mice indicate that IP-10 plays an important nonredundant role in the recruitment of effector T cells into tissue sites in certain inflammatory responses.
In addition to a role in effector T cell trafficking, the data
presented here demonstrate that IP-10 participates in the generation of
effector T cells in vivo. IP-10-/- mice
infected with MHV had fewer Ag-specific IFN--secreting CD8 cells in
the spleen. In addition, following immunization with a model Ag (OVA)
or immunization and challenge with a hapten (DNFB), T cells isolated
from draining lymph nodes had decreased Ag-induced proliferative
response and IFN- secretion. Data from mAb neutralization studies
support this concept. In an IL-12 gene therapy model, mAb
neutralization of IP-10 only during the immunization phase markedly
impaired the generation of tumor-specific effector T cells and
subsequent tumor protective immunity (43). Similarly,
neutralization of IP-10 following acute T. gondii infection
impaired the generation of Ag-specific T cells found in the spleen
(34). Thus, studies using Ab neutralization and
genetically deficient mice have revealed an unexpected role for IP-10
and its receptor CXCR3 in the generation of Ag-specific effector T
cells.
The mechanism(s) by which IP-10 influences the generation of effector T cells has not been established, but published data point in two directions: dendritic cell trafficking and costimulation of T cells. Chemokines guide Ag-loaded dendritic cells from the tissue and naive T cells from the blood into close contact in the lymph node to generate an immune response. SLC (CCL22) and ELC (CCL19) are chemokines that are constitutively expressed in lymphoid tissue and along with their receptor, CCR7, play important roles in this process (59). However, it has become clear that other chemokines, more commonly thought of as inducible chemokines, such as IP-10 and MCP-1, are also constitutively expressed in lymphoid tissue (2, 60) and may also contribute to dendritic cell trafficking. For example, MCP-1 has been shown to play a role in guiding dendritic cells from the periphery into lymph nodes following Ag challenge (61, 62). IP-10 could play a similar role in vivo. In this regard, it is interesting to note that CXCR3 is expressed on plasmacytoid dendritic cells generated following an inflammatory stimulus (22, 63) as well as myeloid dendritic cells found in normal lymph nodes, which have been shown to chemotax in response to IP-10 (23). It has been proposed that constitutive IP-10 expressed in lymph node and spleen attracts Ag-loaded dendritic cells into lymphoid tissue, facilitating dendritic cell and naive T cell interactions, which generate effector T cells (64).
In addition to regulating leukocyte trafficking, chemokines have been suggested to play a role in leukocyte activation. It is well established that chemokines can induce granule release from monocytes, neutrophils, eosinophils, and basophils. Data are also accumulating that chemokines can participate in lymphocyte activation. For example, SDF-1 (CXCL12) is a well-characterized B cell growth factor (65, 66, 67) and has recently been described as a costimulator of T cell activation (68). Our finding that IP-10-/- mice exhibited a decreased allogeneic response is consistent with data reported for the CXCR3-/- mice, which exhibited decreased MLR of similar magnitude (58). These data together with published data demonstrating that activated T cells release IP-10 (2) and that the expression of CXCR3 is increased on T cells following activation in the MLR (69) suggest that IP-10 may costimulate T cell activation in an autocrine loop. However, the contribution of IP-10 to T cell activation can be overcome, because we have previously found that host-derived IP-10 is not essential for the generation of an immune response capable of inducing rejection following allogenic cardiac transplantation (41). The mechanism(s) by which IP-10 may activate T cells is currently unknown. However, a recent report provides evidence that the extracellular signal-regulated kinase pathway may be involved. IP-10 activation of CXCR3 on vascular pericytes was demonstrated to induce proliferation of these cells, and pharmacologic inhibition of the extracellular signal-regulated kinase pathway reduced this response (70).
In summary, we found that IP-10-/- mice exhibit decreased T cell proliferative responses to allogeneic stimulation and decreased T cell priming following primary immunization with exogenous Ag. In vivo studies demonstrated that IP-10-/- mice have a reduced contact hypersensitivity response and impaired host immune response to MHV. In both models this was associated with decreased recruitment of T cells into tissues as well as an impairment in the generation of Ag-specific effector T cells in the periphery. Thus, the generation of IP-10-/- mice has revealed a role for IP-10 in both the generation of effector T cells and their delivery to sites of tissue inflammation.
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Acknowledgments |
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Footnotes |
|---|
2 Current address: Section of Pulmonary and Critical Care, Yale University School of Medicine, New Haven, CT 06520.
3 Current address: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02114.<./>
4 Address correspondence and reprint requests to Dr. Andrew D. Luster, Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129. E-mail address: luster{at}helix.mgh.harvard.edu
5 Abbreviations used in this paper: IP-10, IFN--inducible protein 10; DNFB, 2,4-dinitro-1-fluorobenzene; DNBS, dinitrobenzene sulfonate; ES, embryonic stem; i.c., intracranial(ly); I-TAC, IFN-inducible T cell chemoattractant; LFB, Luxol fast blue; MCP, monocyte chemoattractant protein; MHV, mouse hepatitis virus; Mig, monokine induced by IFN-; p.i., postinfection.
Received for publication October 16, 2001. Accepted for publication January 25, 2002.
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M.-F. Hsieh, S.-L. Lai, J.-P. Chen, J.-M. Sung, Y.-L. Lin, B. A. Wu-Hsieh, C. Gerard, A. Luster, and F. Liao Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus J. Immunol., August 1, 2006; 177(3): 1855 - 1863. [Abstract] [Full Text] [PDF]
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C. N. Renn, D. J. Sanchez, M. T. Ochoa, A. J. Legaspi, C.-K. Oh, P. T. Liu, S. R. Krutzik, P. A. Sieling, G. Cheng, and R. L. Modlin TLR Activation of Langerhans Cell-Like Dendritic Cells Triggers an Antiviral Immune Response J. Immunol., July 1, 2006; 177(1): 298 - 305. [Abstract] [Full Text] [PDF]
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L. Plant, H. Wan, and A.-B. Jonsson MyD88-Dependent Signaling Affects the Development of Meningococcal Sepsis by Nonlipooligosaccharide Ligands. Infect. Immun., June 1, 2006; 74(6): 3538 - 3546. [Abstract] [Full Text] [PDF]
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B. D. Medoff, J. C. Wain, E. Seung, R. Jackobek, T. K. Means, L. C. Ginns, J. M. Farber, and A. D. Luster CXCR3 and Its Ligands in a Murine Model of Obliterative Bronchiolitis: Regulation and Function. J. Immunol., June 1, 2006; 176(11): 7087 - 7095. [Abstract] [Full Text] [PDF]
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M. W. Cruise, J. R. Lukens, A. P. Nguyen, M. G. Lassen, S. N. Waggoner, and Y. S. Hahn Fas Ligand Is Responsible for CXCR3 Chemokine Induction in CD4+ T Cell-Dependent Liver Damage J. Immunol., May 15, 2006; 176(10): 6235 - 6244. [Abstract] [Full Text] [PDF]
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F. Nishimura, J. E. Dusak, J. Eguchi, X. Zhu, A. Gambotto, W. J. Storkus, and H. Okada Adoptive Transfer of Type 1 CTL Mediates Effective Anti-Central Nervous System Tumor Response: Critical Roles of IFN-Inducible Protein-10. Cancer Res., April 15, 2006; 66(8): 4478 - 4487. [Abstract] [Full Text] [PDF]
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C. B. Lopez, J. S. Yount, and T. M. Moran Toll-like receptor-independent triggering of dendritic cell maturation by viruses. J. Virol., April 1, 2006; 80(7): 3128 - 3134. [Full Text] [PDF]
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J. E. Christensen, C. de Lemos, T. Moos, J. P. Christensen, and A. R. Thomsen CXCL10 Is the Key Ligand for CXCR3 on CD8+ Effector T Cells Involved in Immune Surveillance of the Lymphocytic Choriomeningitis Virus-Infected Central Nervous System J. Immunol., April 1, 2006; 176(7): 4235 - 4243. [Abstract] [Full Text] [PDF]
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L. Liu, D. Huang, M. Matsui, T. T. He, T. Hu, J. DeMartino, B. Lu, C. Gerard, and R. M. Ransohoff Severe Disease, Unaltered Leukocyte Migration, and Reduced IFN-{gamma} Production in CXCR3-/- Mice with Experimental Autoimmune Encephalomyelitis J. Immunol., April 1, 2006; 176(7): 4399 - 4409. [Abstract] [Full Text] [PDF]
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C.-N. Chen, S.-F. Chang, P.-L. Lee, K. Chang, L.-J. Chen, S. Usami, S. Chien, and J.-J. Chiu Neutrophils, lymphocytes, and monocytes exhibit diverse behaviors in transendothelial and subendothelial migrations under coculture with smooth muscle cells in disturbed flow Blood, March 1, 2006; 107(5): 1933 - 1942. [Abstract] [Full Text] [PDF]
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 S. R. Weiss and S. Navas-Martin Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus Microbiol. Mol. Biol. Rev., December 1, 2005; 69(4): 635 - 664. [Abstract] [Full Text] [PDF]
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X. Zeng, T. A. Moore, M. W. Newstead, J. C. Deng, S. L. Kunkel, A. D. Luster, and T. J. Standiford Interferon-Inducible Protein 10, but Not Monokine Induced by Gamma Interferon, Promotes Protective Type 1 Immunity in Murine Klebsiella pneumoniae Pneumonia Infect. Immun., December 1, 2005; 73(12): 8226 - 8236. [Abstract] [Full Text] [PDF]
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Q. Liu, L. R. White, S. A. Clark, D. J. Heffner, B. W. Winston, L. A. Tibbles, and D. A. Muruve Akt/Protein Kinase B Activation by Adenovirus Vectors Contributes to NF{kappa}B-Dependent CXCL10 Expression J. Virol., December 1, 2005; 79(23): 14507 - 14515. [Abstract] [Full Text] [PDF]
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B. Nashed, B. Yeganeh, K. T. HayGlass, and M. H. Moghadasian Antiatherogenic Effects of Dietary Plant Sterols Are Associated with Inhibition of Proinflammatory Cytokine Production in Apo E-KO Mice J. Nutr., October 1, 2005; 135(10): 2438 - 2444. [Abstract] [Full Text] [PDF]
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R. S. Klein, E. Lin, B. Zhang, A. D. Luster, J. Tollett, M. A. Samuel, M. Engle, and M. S. Diamond Neuronal CXCL10 Directs CD8+ T-Cell Recruitment and Control of West Nile Virus Encephalitis J. Virol., September 1, 2005; 79(17): 11457 - 11466. [Abstract] [Full Text] [PDF]
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K. Chen, Y. Wei, A. Alter, G. C. Sharp, and H. Braley-Mullen Chemokine expression during development of fibrosis versus resolution in a murine model of granulomatous experimental autoimmune thyroiditis J. Leukoc. Biol., September 1, 2005; 78(3): 716 - 724. [Abstract] [Full Text] [PDF]
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S. M. Curbishley, B. Eksteen, R. P. Gladue, P. Lalor, and D. H. Adams CXCR3 Activation Promotes Lymphocyte Transendothelial Migration across Human Hepatic Endothelium under Fluid Flow Am. J. Pathol., September 1, 2005; 167(3): 887 - 899. [Abstract] [Full Text] [PDF]
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J. Uddin, H. H. Garcia, R. H. Gilman, A. E. Gonzalez, and J. S. Friedland Monocyte-Astrocyte Networks and the Regulation of Chemokine Secretion in Neurocysticercosis J. Immunol., September 1, 2005; 175(5): 3273 - 3281. [Abstract] [Full Text] [PDF]
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N. Ank, K. Petersen, L. Malmgaard, S. C. Mogensen, and S. R. Paludan Age-Dependent Role for CCR5 in Antiviral Host Defense against Herpes Simplex Virus Type 2 J. Virol., August 1, 2005; 79(15): 9831 - 9841. [Abstract] [Full Text] [PDF]
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B. J. Lee, F. Giannoni, A. Lyon, S. Yada, B. Lu, C. Gerard, and S. R. Sarawar Role of CXCR3 in the Immune Response to Murine Gammaherpesvirus 68 J. Virol., July 15, 2005; 79(14): 9351 - 9355. [Abstract] [Full Text] [PDF]
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T. B. Jones, R. P. Hart, and P. G. Popovich Molecular Control of Physiological and Pathological T-Cell Recruitment after Mouse Spinal Cord Injury J. Neurosci., July 13, 2005; 25(28): 6576 - 6583. [Abstract] [Full Text] [PDF]
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J. Wang and I. L. Campbell Innate STAT1-Dependent Genomic Response of Neurons to the Antiviral Cytokine Alpha Interferon J. Virol., July 1, 2005; 79(13): 8295 - 8302. [Abstract] [Full Text] [PDF]
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U. M. Nagarajan, D. M. Ojcius, L. Stahl, R. G. Rank, and T. Darville Chlamydia trachomatis Induces Expression of IFN-{gamma}-Inducible Protein 10 and IFN-{beta} Independent of TLR2 and TLR4, but Largely Dependent on MyD88 J. Immunol., July 1, 2005; 175(1): 450 - 460. [Abstract] [Full Text] [PDF]
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 C. E. Heise, A. Pahuja, S. C. Hudson, M. S. Mistry, A. L. Putnam, M. M. Gross, P. A. Gottlieb, W. S. Wade, M. Kiankarimi, D. Schwarz, et al. Pharmacological Characterization of CXC Chemokine Receptor 3 Ligands and a Small Molecule Antagonist J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1263 - 1271. [Abstract] [Full Text] [PDF]
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G. Li, L. Tian, J.-m. Hou, Z.-y. Ding, Q.-m. He, P. Feng, Y.-j. Wen, F. Xiao, B. Yao, R. Zhang, et al. Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4217 - 4224. [Abstract] [Full Text] [PDF]
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T. Feferman, P. K. Maiti, S. Berrih-Aknin, J. Bismuth, J. Bidault, S. Fuchs, and M. C. Souroujon Overexpression of IFN-Induced Protein 10 and Its Receptor CXCR3 in Myasthenia Gravis J. Immunol., May 1, 2005; 174(9): 5324 - 5331. [Abstract] [Full Text] [PDF]
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J. F. Foley, C.-R. Yu, R. Solow, M. Yacobucci, K. W. C. Peden, and J. M. Farber Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4+ T Cells to HIV-1-Infected Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes J. Immunol., April 15, 2005; 174(8): 4892 - 4900. [Abstract] [Full Text] [PDF]
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Y. Jiang, J. Xu, C. Zhou, Z. Wu, S. Zhong, J. Liu, W. Luo, T. Chen, Q. Qin, and P. Deng Characterization of Cytokine/Chemokine Profiles of Severe Acute Respiratory Syndrome Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 850 - 857. [Abstract] [Full Text] [PDF]
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S. J. Molesworth-Kenyon, J. E. Oakes, and R. N. Lausch A novel role for neutrophils as a source of T cell-recruiting chemokines IP-10 and Mig during the DTH response to HSV-1 antigen J. Leukoc. Biol., April 1, 2005; 77(4): 552 - 559. [Abstract] [Full Text] [PDF]
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A. Saudemont, N. Jouy, D. Hetuin, and B. Quesnel NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells Blood, March 15, 2005; 105(6): 2428 - 2435. [Abstract] [Full Text] [PDF]
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M. Ejrnaes, N. Videbaek, U. Christen, A. Cooke, B. K. Michelsen, and M. von Herrath Different Diabetogenic Potential of Autoaggressive CD8+ Clones Associated with IFN-{gamma}-Inducible Protein 10 (CXC Chemokine Ligand 10) Production but Not Cytokine Expression, Cytolytic Activity, or Homing Characteristics J. Immunol., March 1, 2005; 174(5): 2746 - 2755. [Abstract] [Full Text] [PDF]
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D. Zipris, E. Lien, J. X. Xie, D. L. Greiner, J. P. Mordes, and A. A. Rossini TLR Activation Synergizes with Kilham Rat Virus Infection to Induce Diabetes in BBDR Rats J. Immunol., January 1, 2005; 174(1): 131 - 142. [Abstract] [Full Text] [PDF]
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 A. M. Tager, R. L. Kradin, P. LaCamera, S. D. Bercury, G. S. V. Campanella, C. P. Leary, V. Polosukhin, L.-H. Zhao, H. Sakamoto, T. S. Blackwell, et al. Inhibition of Pulmonary Fibrosis by the Chemokine IP-10/CXCL10 Am. J. Respir. Cell Mol. Biol., October 1, 2004; 31(4): 395 - 404. [Abstract] [Full Text] [PDF]
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R. A. Colvin, G. S. V. Campanella, J. Sun, and A. D. Luster Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function J. Biol. Chem., July 16, 2004; 279(29): 30219 - 30227. [Abstract] [Full Text] [PDF]
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M. S. Thomas, S. L. Kunkel, and N. W. Lukacs Regulation of Cockroach Antigen-Induced Allergic Airway Hyperreactivity by the CXCR3 Ligand CXCL9 J. Immunol., July 1, 2004; 173(1): 615 - 623. [Abstract] [Full Text] [PDF]
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D. Whiting, G. Hsieh, J. J. Yun, A. Banerji, W. Yao, M. C. Fishbein, J. Belperio, R. M. Strieter, B. Bonavida, and A. Ardehali Chemokine Monokine Induced by IFN-{gamma}/CXC Chemokine Ligand 9 Stimulates T Lymphocyte Proliferation and Effector Cytokine Production J. Immunol., June 15, 2004; 172(12): 7417 - 7424. [Abstract] [Full Text] [PDF]
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J. E. Christensen, A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen Efficient T-Cell Surveillance of the CNS Requires Expression of the CXC Chemokine Receptor 3 J. Neurosci., May 19, 2004; 24(20): 4849 - 4858. [Abstract] [Full Text] [PDF]
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B. Raju, Y. Hoshino, K. Kuwabara, I. Belitskaya, S. Prabhakar, A. Canova, J. A. Gold, R. Condos, R. I. Pine, S. Brown, et al. Aerosolized Gamma Interferon (IFN-{gamma}) Induces Expression of the Genes Encoding the IFN-{gamma}-Inducible 10-Kilodalton Protein but Not Inducible Nitric Oxide Synthase in the Lung during Tuberculosis Infect. Immun., March 1, 2004; 72(3): 1275 - 1283. [Abstract] [Full Text] [PDF]
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C. L. Afonso, M. E. Piccone, K. M. Zaffuto, J. Neilan, G. F. Kutish, Z. Lu, C. A. Balinsky, T. R. Gibb, T. J. Bean, L. Zsak, et al. African Swine Fever Virus Multigene Family 360 and 530 Genes Affect Host Interferon Response J. Virol., February 15, 2004; 78(4): 1858 - 1864. [Abstract] [Full Text] [PDF]
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 I. Tsunoda, T. E Lane, J. Blackett, and R. S Fujinami Distinct roles for IP-10/C XC L10 in three animal models, Theiler's virus infection, EA E, and MHV infection, for multiple sclerosis: implication of differing roles for IP-10 Multiple Sclerosis, February 1, 2004; 10(1): 26 - 34. [Abstract] [PDF]
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M. J. Trifilo, C. Montalto-Morrison, L. N. Stiles, K. R. Hurst, J. L. Hardison, J. E. Manning, P. S. Masters, and T. E. Lane CXC Chemokine Ligand 10 Controls Viral Infection in the Central Nervous System: Evidence for a Role in Innate Immune Response through Recruitment and Activation of Natural Killer Cells J. Virol., January 15, 2004; 78(2): 585 - 594. [Abstract] [Full Text] [PDF]
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K. Abel, L. La Franco-Scheuch, T. Rourke, Z.-M. Ma, V. de Silva, B. Fallert, L. Beckett, T. A. Reinhart, and C. J. Miller Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques J. Virol., January 15, 2004; 78(2): 841 - 854. [Abstract] [Full Text] [PDF]
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R. S. Klein, L. Izikson, T. Means, H. D. Gibson, E. Lin, R. A. Sobel, H. L. Weiner, and A. D. Luster IFN-Inducible Protein 10/CXC Chemokine Ligand 10-Independent Induction of Experimental Autoimmune Encephalomyelitis J. Immunol., January 1, 2004; 172(1): 550 - 559. [Abstract] [Full Text] [PDF]
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U. Christen, D. B. McGavern, A. D. Luster, M. G. von Herrath, and M. B. A. Oldstone Among CXCR3 Chemokines, IFN-{gamma}-Inducible Protein of 10 kDa (CXC Chemokine Ligand (CXCL) 10) but Not Monokine Induced by IFN-{gamma} (CXCL9) Imprints a Pattern for the Subsequent Development of Autoimmune Disease J. Immunol., December 15, 2003; 171(12): 6838 - 6845. [Abstract] [Full Text] [PDF]
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G. D. Han, H. Koike, T. Nakatsue, K. Suzuki, H. Yoneyama, S. Narumi, N. Kobayashi, P. Mundel, F. Shimizu, and H. Kawachi IFN-Inducible Protein-10 Has a Differential Role in Podocyte during Thy 1.1 Glomerulonephritis J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3111 - 3126. [Abstract] [Full Text] [PDF]
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C. M. U. Hilkens, J. F. Schlaak, and I. M. Kerr Differential Responses to IFN-{alpha} Subtypes in Human T Cells and Dendritic Cells J. Immunol., November 15, 2003; 171(10): 5255 - 5263. [Abstract] [Full Text] [PDF]
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G. Valbuena, W. Bradford, and D. H. Walker Expression Analysis of the T-Cell-Targeting Chemokines CXCL9 and CXCL10 in Mice and Humans with Endothelial Infections Caused by Rickettsiae of the Spotted Fever Group Am. J. Pathol., October 1, 2003; 163(4): 1357 - 1369. [Abstract] [Full Text] [PDF]
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D. J. J. Carr, J. Chodosh, J. Ash, and T. E. Lane Effect of Anti-CXCL10 Monoclonal Antibody on Herpes Simplex Virus Type 1 Keratitis and Retinal Infection J. Virol., September 15, 2003; 77(18): 10037 - 10046. [Abstract] [Full Text] [PDF]
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R. L. Rabin, M. A. Alston, J. C. Sircus, B. Knollmann-Ritschel, C. Moratz, D. Ngo, and J. M. Farber CXCR3 Is Induced Early on the Pathway of CD4+ T Cell Differentiation and Bridges Central and Peripheral Functions J. Immunol., September 15, 2003; 171(6): 2812 - 2824. [Abstract] [Full Text] [PDF]
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B. Johnston, C. H. Kim, D. Soler, M. Emoto, and E. C. Butcher Differential Chemokine Responses and Homing Patterns of Murine TCR{alpha}{beta} NKT Cell Subsets J. Immunol., September 15, 2003; 171(6): 2960 - 2969. [Abstract] [Full Text] [PDF]
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 S Futagami, T Hiratsuka, A Tatsuguchi, K Suzuki, M Kusunoki, Y Shinji, K Shinoki, T Iizumi, T Akamatsu, H Nishigaki, et al. Monocyte chemoattractant protein 1 (MCP-1) released from Helicobacter pylori stimulated gastric epithelial cells induces cyclooxygenase 2 expression and activation in T cells Gut, September 1, 2003; 52(9): 1257 - 1264. [Abstract] [Full Text]
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J. Melchjorsen, L. N. Sorensen, and S. R. Paludan Expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function J. Leukoc. Biol., September 1, 2003; 74(3): 331 - 343. [Abstract] [Full Text] [PDF]
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E. M. Genden, A. Iskander, J. S. Bromberg, and L. Mayer The Kinetics and Pattern of Tracheal Allograft Re-Epithelialization Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 673 - 681. [Abstract] [Full Text] [PDF]
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G. S. V. Campanella, E. M. J. Lee, J. Sun, and A. D. Luster CXCR3 and Heparin Binding Sites of the Chemokine IP-10 (CXCL10) J. Biol. Chem., May 2, 2003; 278(19): 17066 - 17074. [Abstract] [Full Text] [PDF]
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M. C.-J. Cheeran, S. Hu, W. S. Sheng, P. K. Peterson, and J. R. Lokensgard CXCL10 Production from Cytomegalovirus-Stimulated Microglia Is Regulated by both Human and Viral Interleukin-10 J. Virol., April 15, 2003; 77(8): 4502 - 4515. [Abstract] [Full Text] [PDF]
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 S. Nakae, Y. Komiyama, S. Narumi, K. Sudo, R. Horai, Y.-i. Tagawa, K. Sekikawa, K. Matsushima, M. Asano, and Y. Iwakura IL-1-induced tumor necrosis factor-{alpha} elicits inflammatory cell infiltration in the skin by inducing IFN-{gamma}-inducible protein 10 in the elicitation phase of the contact hypersensitivity response Int. Immunol., February 1, 2003; 15(2): 251 - 260. [Abstract] [Full Text] [PDF]
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C. M. Denkinger, M. Denkinger, J. J. Kort, C. Metz, and T. G. Forsthuber In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System J. Immunol., February 1, 2003; 170(3): 1274 - 1282. [Abstract] [Full Text] [PDF]
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) were deleted and replaced by the neomycin
resistance gene driven by the phosphoglycerate kinase promoter
(PGK-neo). Negative selection was provided by the thymidine kinase gene
driven by the HSV promoter. Relevant restriction endonuclease sites are
indicated: B, BamHI; E, EcoRI; RV,
EcoRV; S, SalI; X, XbaI;
Xh, XhoI. B, Southern blot analysis of
DNA isolated from IP-10 wild-type (+/+), IP-10 heterozygous (+/-), and
IP-10 homozygous (-/-) mice for the disrupted IP-10 allele. DNA was
digested using XbaI and was analyzed by Southern
blotting using the probe indicated in A. The wild-type
allele migrates as a 2-kb hybridizing fragment and the disrupted allele
as a 2.7-kb hybridizing band. C, Northern blot analysis
of chemokine expression. RNA was harvested from bone marrow macrophages
isolated from IP-10+/+, IP-10+/-, and
IP-10-/- mice; stimulated with medium control, IFN-
