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*
Committee on Immunology and
Section of Pulmonary and Critical Care, Department of Medicine, and
Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, 60637;
Alexion Pharmaceuticals, New Haven, CT 06511; and
¶ Department of Medicine, University of Iowa, Iowa City, IA 52242
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-
, and GM-CSF secretion. However,
unlike CD28, ICOS costimulation has not been shown to dramatically
augment IL-2 production (1, 4). The initial studies on
ICOS demonstrated the absence of the B7-binding MYPPPY motif that is
found in CD28 and CTLA-4, suggesting that ICOS was not a receptor for
B71/B72. Subsequently, it has been shown that a novel B7-like molecule
termed B7-related protein-1 (B7RP-1) (also referred to as B7h,
GL50, and LICOS; Refs. 2, 5, 6, 7, 8) binds to ICOS. B7RP-1
shares 
20% identity with B71/B72 and is expressed on both normal
and sensitized APCs, whereas B71/2 molecules are up-regulated on
activated cells. The majority of naive T cells will express ICOS after activation. However, Th2 cells continue to express ICOS, whereas Th1 cells have decreased expression (9, 10). Studies have suggested that signaling through ICOS may induce Th2 cell differentiation (1, 9, 11, 12, 13), and in vivo analysis from several groups demonstrate that ICOS-mediated costimulation may also regulate Th2 effector cells (10, 14). In the present study, we have examined the role of ICOS in a Th2-dependent model of allergic airway disease (AAD) induced by sensitization with expired Schistosoma mansoni eggs and local antigenic challenge with S. mansoni soluble egg Ag (SEA) in the lungs. Injection of S. mansoni eggs i.p. has been shown to result in early T cell-independent IL-4 production within the periphery (15, 16). As activated precursor T cells expand, this IL-4 production leads to polarization toward a Th2 lineage. These T cells can be found in both the primary and secondary lymphoid organs and produce Th2 cytokines when restimulated with SEA in culture (17). In addition, a strong IgE response, a characteristic trait of parasitic infections, is induced by S. mansoni egg injection (17). In our model of AAD, we use the Th2-skewing effect of S. mansoni eggs by immunizing with inactivated eggs that do not induce an infection. Following challenge in the lungs with purified SEA, local cells respond by making chemokines and cytokines that in turn cause Th2 cells to enter the site of challenge (18). Cytokines, such as IL-5, lead to the eosinophilia, which is a hallmark of allergic airway inflammation. Other physiologic features of AAD include goblet cell hyperplasia, smooth muscle hyperplasia, and excess mucous production within the lungs (19). We have shown that both the initial sensitization with S. mansoni eggs and the subsequent challenge with SEA are necessary to achieve eosinophilic inflammation in the lung (20). However, IgE levels are increased following i.p. sensitization alone, suggesting that activated systemic Th2 cells provide help for B cells.
In previous studies, we demonstrated that CD28 blockade inhibits Th2-mediated inflammation by skewing the response normally made to S. mansoni from a Th2 phenotype toward a Th1 phenotype (20). These results suggested that CD28 signaling was important during the primary immune response. Thus, it was of interest to examine the effect of ICOS blockade on the response made during primary stimulation. To test whether ICOS/B7RP-1 interactions are required for promoting Th2 inflammatory responses, mice received an i.p. injection of ICOS-Ig, a soluble form of ICOS, during sensitization and challenge. In this system, we found decreased airway inflammation in ICOS-Ig-treated mice as compared with control mice. Interestingly, unlike CTLA4-Ig treatment, no change in T cell priming or differentiation was observed when mice are treated with ICOS-Ig. Cytokine production from restimulation of ex vivo Th2 effector lung cells was inhibited by ICOS-Ig. These results suggest that ICOS-mediated costimulation may regulate Th2 effector cell function without affecting Th2 differentiation to a Th2-type antigenic stimulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female 4- to 6-wk-old C57BL/6 mice were purchased from The Division of Cancer Treatment at the National Cancer Institute (Frederick, MD). Animals were housed in a specific pathogen-free biohazard level 2 facility maintained by the University of Chicago Animal Resources Center (Chicago, IL). The studies detailed herein conform to the principles set forth by the Animal Welfare Act and the National Institutes of Health guidelines for the care and use of animals in biomedical research.
Cloning of ICOS and production of rICOS-Ig
A partial amino acid sequence containing homology with CD28 and
CTLA-4 was obtained by searching the murine expressed sequence
tag database with CD28 or CTLA-4 protein sequences as queries
using the tblastn program found on the National Center for
Biotechnology Information website (http://www.ncbi.nlm.nih.gov/).
Two gene-specific PCR primers were designed based on the expressed
sequence tag nucleic acid sequence, and 5' and 3' RACE were performed
on mouse spleen Marathon-Ready cDNA as described in the manufacturer’s
protocol (Clontech, Palo Alto, CA). PCR products were cloned into the
pCR2.1-TOPO vector using the TOPO TA cloning kit (Invitrogen, Carlsbad,
CA) and sequenced by the DNA Sequencing and Synthesis Facility (Iowa
State University, Ames, IA). Full-length ICOS cDNA was obtained by PCR
using the mouse spleen Marathon-Ready cDNA as a template and primers
that flanked the start and stop codons of the molecule. The construct
for ICOS-Ig was made by fusing the extracelluar region of murine ICOS
(1–427 bp) to the CH2 and CH3 regions of murine IgG2a Fc in the
eukaryotic expression vector pcDNA3.1+. The construct was
expressed in HEK 293/TSA-O-A cells. Cells were maintained in a
RESCU-Primer bioreactor (Cellex Biosciences, Minneapolis, MN) and grown
in 1.25% complete medium (DMEM, 1.25% heat-inactivated FCS, 25 µM
HEPES, 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml
streptomycin, 2 mM nonessential amino acids, and 5 x
10-5 M 
2-ME). ICOS-Ig was purified by passing
the harvest supernatant over a protein A column (Repligen, Boston, MA)
using standard techniques.
Ag sensitization and challenge
Inactivated S. mansoni eggs and Ag were prepared as previously described (21, 22). The protocol used for animal sensitization and challenge was modified from that of Padrid et al. (20) and Lukacs et al. (23). Briefly, mice were immunized i.p. on day 0 with 5 x 103 inactivated S. mansoni eggs. Mice were challenged on day 7 via intratracheal delivery of 10 µg SEA. Previously, we have found that AAD is not induced in mice left unchallenged or challenged with PBS only (20). Where indicated, mice received an i.p. injection of either 50 µg ICOS-Ig, 100 µg ICOS-Ig, 1x sterile PBS, or 50 µg IgG2a (Southern Biotechnology Associates, Birmingham, AL) beginning the day before S. mansoni egg sensitization (day -1) and every other day thereafter (days 1, 3, 5, 7, and 9) until animals were sacrificed on day 11.
Bronchoalveolar lavage (BAL)
Mice were sacrificed on days 4–6 after challenge via i.p. injection of 30 mg/mouse ketamine-HCl. We have found that airway inflammation peaks on these days in our model and is completely resolved by 14 days after intratracheal challenge (A. M. Frantz and A. I. Sperling, unpublished observations). BAL was performed by delivering 0.8 ml cold PBS into the airway via a trachea cannula and gently aspirating the fluid. The lavage was repeated three times to recover a total volume of 2–3 ml. The cells were stained with trypan blue to determine viability, and total nucleated cell counts were obtained using a hemocytometer. Cytospin slides were prepared from the BAL and were then fixed and stained using Diff-Quick (Dade Diagnostics, Aguada, PR). Differential cell counts were determined by counting a minimum of 200 cells/slide using standard morphological criteria. The total number of eosinophils, macrophages, and lymphocytes were calculated as follows: (total number of nucleated cells within airway) x (percentage of cell type within airway). The percentage of cell types found within the BAL fluid was calculated as follows: (number of cell type)/(total number of cells within cytospin).
Histology
A portion of the lung was fixed in 4% paraformaldehyde. Lobes were sectioned sagitally, embedded in paraffin, cut into 5-µm sections, and stained with H&E for routine analysis. Scoring was based on the intensity of inflammation on a scale of 0–5, with 0 being negative for airway inflammation and 5 being the most severe. Lungs were considered inflamed if the following were detected: eosinophilic and lymphocytic infiltration around bronchioles and vessels, as well as goblet-cell hyperplasia and smooth muscle thickening. The slides were coded and scored blindly to prevent bias.
Isolation of lung lymphocytes
Lungs were disassociated by agitating the tissue for 1 h in 20 ml digestion buffer (hyaluronidase at 85 U/ml (Sigma, St. Louis, MO), DNaseI at 50 U/ml (Boehinger Mannheim, Mannheim, Germany), and collagenase P at 1.0 mg/ml (Boehringer Manheim)). The digest was passed through nytex filter, and RBCs were depleted with ammonium chloride-potassium lysing buffer. To enrich for lymphocytes, cells were centrifuged through a Percoll step gradient (Amersham Pharmacia Biotech, Uppsala, Sweden). The cells at the 50–75% interface were collected and washed in 5% complete medium.
Lung lymphocytes and splenocyte restimulation ex vivo
Cells were plated at 2 x 105 cells/well (lung cells) or 4 x 105 cells/well (splenocytes) in a 96-well U-bottom plate. T cell-depleted, irradiated splenocytes (APCs) were mixed with lung cells at a 1:1 ratio. Cells were cultured with SEA (10 µg/ml), IgG2a (20 µg/ml), or ICOS-Ig (20 µg/ml) as indicated in the text. The final volume of all wells was 200 µl. Plates were incubated for 48 h, after which time the supernatants were collected for cytokine analysis by ELISA. Percentage of inhibition of cytokine production in the presence of ICOS-Ig or in the presence of an isotype control was calculated by first subtracting the spontaneous cytokine production from the levels with SEA and then determining the percentage of inhibition with ICOS-Ig or control IgG2a. To assess proliferation, additional plates were pulsed with 1 µCi/well of [3H]thymidine at 48 h and harvested 8–12 h later.
Cytokine analysis
Cytokine production by lung lymphocytes and splenocytes was measured by ELISA according to the manufacturer’s protocol (BD PharMingen, San Diego, CA.). Sera were collected by cardiac puncture and used to measure total serum IgE levels by ELISA (BD PharMingen).
Statistical analysis
All statistics were done using an upaired Student two-tailed t test. Error bars represent SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To induce airway inflammation, female C57BL/6 mice were sensitized
i.p. on day 0 with 5 x 103 inactivated
S. mansoni eggs, and on day 7, the mice were challenged with
10 µg SEA delivered by intratracheal instillation. In addition, mice
were treated with nothing, PBS (data not shown), 50 µg ICOS-Ig, or
with an IgG2a isotype control on days -1, 1, 3, 5, 7, and 9.
Throughout our studies, we found that treatment with nothing, PBS, or
an IgG2a isotype control gave similar results (Fig. 1
A and data not shown);
therefore, not all controls were used for each experiment. On day 11,
the animals were sacrificed and analyzed for airway inflammation. Total
nucleated cell counts were determined from the BAL fluid recovered from
the airways. A 66–73% decrease in the severity of inflammation within
the airways was found in ICOS-Ig-treated animals compared with control
Ig-treated animals and untreated animals, respectively (Fig. 1A). Thus, blockade of ICOS-mediated costimulation
dramatically reduced cellular infiltration of cells into the airways of
inflamed lungs.
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B). The number of macrophages followed the trend of
decreased cell number (39% decrease), although the difference was not
statistically significant compared with control mice. These data are
supported by the finding that local IL-5 production measured in the BAL
fluid from SCH mice was lower in the ICOS-Ig-treated group vs the
control group (Fig. 1C).
Although the total number of cells was decreased, the percentages of
eosinophils, macrophages, and lymphocytes found within the BAL of
ICOS-Ig-treated mice were similar to those found in the BAL of
control-treated animals (Fig. 1D). These results are in
contrast to previous observations in a similar experimental model
system, where treatment with CTLA4-Ig not only blocked total
inflammation, but also significantly lowered the relative percentages
of eosinophils found while increasing the number of lymphocytes
(20). Thus, treatment with ICOS-Ig did not selectively
alter the Th2 phenotype of the inflammatory response, but rather
diminished the severity of the inflammation.
The attenuated severity of inflammation in ICOS-Ig-treated animals was
further supported by experiments to evaluate inflammation by
histological analysis of lung sections (Fig. 2). Lung sections were scored for
infiltration based on a system previously described in detail by Padrid
et al. (20). Briefly, the lungs are scored on a scale of
0–5, in which a score of 0 was given when there is no inflammation,
and a score of 5 was given when massive infiltration is found around
both the vessels and the bronchioles. Because inflammation can vary
from lobe to lobe, each lobe was scored separately, and an average
inflammatory score was obtained for the entire lung tissue. Both
control and ICOS-Ig-treated lungs displayed characteristics typical of
lung inflammation, including eosinophilic and lymphocytic infiltration
around bronchioles and vessels as well as goblet-cell hyperplasia and
smooth muscle thickening (data not shown). However, the extent of
infiltration was markedly reduced in ICOS-Ig-treated lungs as compared
with those from control-treated mice.
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One possible explanation for the observed decrease in inflammation
with ICOS-Ig treatment is that blockade of ICOS-mediated costimulation
during sensitization inhibits T cell priming to Ag. Alternatively, the
blockade of ICOS costimulation may lead to the induction of T cell
anergy. To investigate these possibilities, splenocytes from mice SCH
in the presence or absence of ICOS-Ig were examined for their ability
to respond to restimulation with SEA ex vivo. Total splenocytes from
SCH mice were cultured either with SEA or medium alone, and
proliferation was measured by [3H]thymidine
uptake. No differences in proliferation were observed (Fig. 3A). These data suggest that
ICOS-Ig treatment did not induce T cell anergy, nor did it block T cell
priming to SEA.
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B). Together, these results demonstrate that blockade of
ICOS-mediated costimulation throughout sensitization did not affect the
ability of systemic T cells to be activated by Ag or to differentiate
into Th2-type cells. Blockade of ICOS costimulation does not affect serum IgE levels
In addition to eosinophilia, elevated levels of serum IgE are
indicative of a Th2 response to S. mansoni eggs. However,
whereas the number of eosinophils was decreased by ICOS-Ig treatment,
there was no statistically significant difference in the levels of IgE
in ICOS-Ig-treated vs control animals (Fig. 4). Nevertheless, ICOS-Ig-treated mice
were found to have reduced levels of IgE (3000 vs 4700 ng/ml in
control-treated mice). These data suggest that B cells are still
capable of being activated during the primary response; thus, Ig class
switching is not prevented in the absence of ICOS signaling.
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The results presented thus far have demonstrated that
ICOS-mediated costimulation is not required for development of Th2
immune responses following the initial sensitization to S.
mansoni eggs. Rather, our data revealed that ICOS-Ig treatment
severely inhibits airway inflammation, suggesting that ICOS-mediated
costimulation may play a role in the function of differentiated Th2
cells in the present model of AAD. To test whether T cells that make it
to the lung tissue under ICOS blockade are able to produce Th2
cytokines, T cells isolated from ICOS-Ig-treated and untreated inflamed
lung tissue were restimulated in vitro with SEA. We found that ex vivo
restimulation of T cells from the inflamed lungs of ICOS-Ig-treated
mice resulted in the production of significant amounts of the Th2
cytokine IL-5 (Fig. 5). There was no
increase in the Th1-type cytokine IFN-, which remained below the
level of detection (data not shown). These data suggest that S.
mansoni-specific Th2 cells that have migrated to the lungs in
response to challenge are capable of effector functions. However, in
the absence of ICOS signaling, far fewer cells successfully enter the
lungs following secondary stimulation with Ag (Fig. 1B).
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was undetectable (Fig. 6 and data not
shown). This Ag-specific response was strongly inhibited by the
addition of ICOS-Ig to the culture, but not by the presence of an
irrelevant IgG2a mAb. Therefore, ICOS-mediated costimulation regulates
Th2 cytokine production upon restimulation with Ag. We also observed
this effect in splenocytes isolated from these mice (data not shown),
suggesting that the effect of ICOS-B7RP-1 blockade is not tissue
specific, but rather, that ICOS signaling is generally important for
the effector function of Th2 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B). In contrast to recent
reports (1, 9), these results suggest that ICOS-mediated
costimulation does not alter the ability of precursor Th cells to
proliferate and differentiate into Th2 effector cells. It is possible
that, because S. mansoni is a potent Th2-inducing Ag, the
blockade of ICOS-B7RP-1 interactions may not be strong enough to
prevent the development of Th2 cells in our in vivo model. It is also
possible that the ICOS-Ig used in these experiments did not completely
prevent the interaction between ICOS and B7RP-1. However, ICOS-B7RP-1
blockade did lead to a reduction in the number of Th2 cells and
eosinophils infiltrating the lungs following local challenge with SEA.
These data suggest that Th2 function such as cytokine production and/or
Th2 migration may be more sensitive to ICOS blockade than to Th2
differentiation. The decrease in IL-5 production could, for instance,
explain the decrease in eosinophilia within the inflamed lungs, whereas
a decrease in responsiveness to chemokines could explain the decrease
in Th2 cells that are recruited to the lung following challenge.
Together, these events may offer an explanation for the decreased
inflammation and lung eosinophilia observed in ICOS-Ig-treated
mice.
Serum IgE levels, which are increased due to S. mansoni
infection, were not significantly decreased in ICOS-Ig-treated mice
(Fig. 4). We and others have found that high serum IgE levels can be
found in mice that have been sensitized but not challenged (data not
shown and Ref. 17), suggesting that much of the IgE
response can be attributed to the primary response to S.
mansoni eggs. Thus, the inability of ICOS-Ig to block IgE
production is consistent with our findings that ICOS costimulation is
not required for the primary Th2 response to S. mansoni
eggs. Likewise, Coyle et al. (10) have shown that ICOS
blockade does not inhibit Ig production upon primary stimulation.
Similarly, Kopf et al. (14) found that there was no
inhibition of IgG subclasses when mice infected with lymphocytic
choriomeningitis virus were treated with ICOS-Ig during the course of
the infection. Although Hutloff et al. (1) found that
ICOS-B7RP-1 interactions induced up-regulation of CD40 ligand on T
cells, and Coyle et al. (10) showed that ICOS blockade
partially inhibits some isotypes after secondary immunization, our data
support recent studies that suggest that this signaling cascade is not
exclusively required for T cell help of Ig switching and
production.
Recent reports have shown a defect in the ability of
ICOS-/- mice to mount a Th2 response
(11, 12, 13). In particular, IL-4 and IgE production seem to
be defective in culture and in vivo, whereas IFN- is either
augmented or equal in the ICOS-/- mice. The
defect in Th2 differentiation could be overcome in part by the addition
of exogenous IL-4 in vitro or by the use of a strong adjuvant in vivo.
In our model, we use a strong Th2-inducing Ag. In addition, it has been
found that S. mansoni egg injection into the peritoneal
cavity results in early IL-4 production that is not due to
CD4+ T cells, and in fact, may be the result of
an innate immune response by mast cells to the parasitic Ag
(15). This early, "exogenous" IL-4 may serve to skew
CD4+ T helper precursors toward a Th2
phenotype and account for the development of Th2 cells in the absence
of ICOS signaling. Our data suggest that although differentiation of
Th2 cells can be accomplished in the absence of ICOS signaling, the
requirement for ICOS costimulation for Th2 effector function is more
stringent.
Blockade of ICOS signaling resulted in decreased severity of
inflammation in our model. Interestingly, although the total number of
cells recovered from the airway was reduced in the ICOS-Ig-treated
group, the percentage of the various cell populations recovered from
the BAL did not differ from that of control mice (Fig. 1D).
These results differ from experiments that examined the role of
CD28-mediated costimulation in airway inflammation. In those studies,
the airway inflammation was not only reduced, but the cellular
composition of the inflammation was significantly altered
(20); CTLA4-Ig treatment led to a decrease in eosinophil
infiltration with a concomitant increase in lymphocytic infiltration.
In addition, restimulated lung T cells exhibited reduced Th2 cytokine
production, whereas Th1 (IFN-) cytokine production was enhanced
(20). In contrast, treatment of mice with ICOS-Ig did not
change the cytokine profile produced by the lung lymphocytes upon ex
vivo restimulation when the total T cell numbers in each well were
equalized between samples (Fig. 5). Thus, our data suggest that Th2
development was not effected by ICOS blockade. This finding is in
direct contrast to those presented by Kopf et al. (14). In
those studies, ICOS-Ig treatment was found to cause a slight decrease
in the development of Th2 cells in response to the nematode
Nippostrongylus brasiliensis. It should be noted that
the two systems differ in many ways, such as the types of Ag used, as
well as in the administration of ICOS-Ig (i.v. vs i.p.).
Th2 effector functions, such as cytokine production, were shown to be
dependent on ICOS-mediated costimulation (Fig. 6). This suggests that
Th2 cells that successfully migrate to the site of challenge upon
restimulation with Ag may produce less cytokines in the absence of ICOS
signaling. Decreased cytokine production in the lungs by the
residual Th2 cells could have a profound effect on the recruitment of
additional Th2 cells as well as eosinophils into the tissue. Li et al.
(18) have shown that supernatant from Th2 cells, when
instilled directly in to the lungs, can induce chemokine production and
the recruitment of eosinophils. IL-13, for example, can induce eotaxin
expression by epithelial cells, and local production of IL-5 has been
demonstrated to be necessary for effective migration of eosinophils
(18, 28). Thus, blockade of ICOS-B7RP-1 interactions may
result in fewer cytokine-producing T cells migrating into the lung
tissue and, therefore, to a decrease in eosinophilia. However, the
effect of ICOS-Ig on cytokine production that was observed in vitro may
not fully correspond to an in vivo situation. For instance, in vivo
ICOS-Ig may be less potent due to protein degradation or to a lower
"final" concentration, whereas, in vitro, these issues are less of
a concern. Furthermore, we cannot rule out the possibility that the
observed decrease in cellular infiltration (Fig. 1B)
is due to Th2 cells that may be less receptive to chemokines. Studies
have shown differences in the ability of Th1/Th2 cells to respond to
chemokines. For example, CCR7, which recognizes secondary lymphoid
chemokine and EB11-ligand chemokine, is specifically expressed
on Th1 cells (29), whereas CCR3 and CCR4 have been
implicated in the recruitment of Th2 cells to the lungs during allergic
inflammation (30). Thus, it is possible that ICOS
signaling is important for the up-regulation of specific Th2 chemokine
receptors.
Coyle et al. (10) have found that ICOS-Ig treatment of mice in an adoptive transfer model of airway inflammation effectively blocked the Th2-type eosinophilic, but not the Th1-type neutrophilic, inflammatory response. In their model, the T cells were first differentiated in vitro. The resulting Th1 and Th2 populations were independently transferred into naive BALB/c recipients that were then challenged with inhaled Ag. Their finding that ICOS signaling is important in the migration and/or function of these effector Th2 cells supports our findings. We have further demonstrated that ICOS blockade can significantly decrease inflammation without affecting Th2 differentiation. Together, these data suggest that ICOS signaling may play a more important role in effector function than in Th2 differentiation.
In contrast to the findings presented herein and the studies of Coyle and colleagues, Dong et al. (11) found that the absence of ICOS (in ICOS-/- mice) did not lead to a significant reduction in the number of eosinophils and lymphocytes within the airways of mice with OVA-induced AAD. T cells from the mediastinal lymph nodes made less IL-4 and IL-13 when restimulated, as compared with wild-type cells, whereas no defect in IL-5 production was noted. The reasons for the difference between the results with the ICOS-/- mice and the ICOS-Ig administration remain to be determined. It is possible that the effect of blocking ICOS function on normally differentiated ICOS-sufficient Th2 cells may be completely different from what is seen in the ICOS-/- mice. In these mice, the "Th2-type" response is abnormal because the T cells make no IL-4, little IL-13, and normal levels of IL-5. These cells may not be conventional Th2 cells, but an alternative type of response that is not normally predominant in the presence of ICOS signaling. Additional experiments are required to definitively resolve these apparently contradictory findings.
Our data have important implications for the treatment of patients with asthma or with other Th2-related conditions. As opposed to immune suppressants that disrupt all immune responses, ICOS blockade may only affect migration and effector function of Ag-specific Th2 cells activated during secondary stimulation in an allergic response. Thus, our findings that ICOS and B7RP-1 are involved in sustaining a Th2 response during restimulation may lead to the development of useful therapeutics for Th2 diseases.
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Acknowledgments |
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Footnotes |
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2 Current address: Diabetes Center, University of California, San Francisco, CA 94143
3 Address correspondence and reprint requests to Dr. Anne I. Sperling, University of Chicago, MC6026 M624, 5841 South Maryland Avenue, Chicago, IL 60637. E-mail address: asperlin{at}medicine.bsd.uchicago.edu
4 Abbreviations used in this paper: ICOS, inducible costimulator; B7RP-1, B7-related protein-1; AAD, allergic airway disease; SCH, sensitized and challenged; SEA, Schistosoma mansoni soluble egg Ag; BAL bronchoalveolar lavage.
Received for publication December 26, 2000. Accepted for publication June 4, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, but not on eosinophils. J. Immunol. 162:6178.This article has been cited by other articles:
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  J. M. Odegard, L. D. DiPlacido, L. Greenwald, M. Kashgarian, D. H. Kono, C. Dong, R. A. Flavell, and J. Craft ICOS Controls Effector Function but Not Trafficking Receptor Expression of Kidney-Infiltrating Effector T Cells in Murine Lupus J. Immunol., April 1, 2009; 182(7): 4076 - 4084. [Abstract] [Full Text] [PDF]
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M. Watanabe, Y. Takagi, M. Kotani, Y. Hara, A. Inamine, K. Hayashi, S. Ogawa, K. Takeda, K. Tanabe, and R. Abe Down-Regulation of ICOS Ligand by Interaction with ICOS Functions as a Regulatory Mechanism for Immune Responses J. Immunol., April 15, 2008; 180(8): 5222 - 5234. [Abstract] [Full Text] [PDF]
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T. Kallinich, K. C. Beier, U. Wahn, P. Stock, and E. Hamelmann T-cell co-stimulatory molecules: their role in allergic immune reactions Eur. Respir. J., June 1, 2007; 29(6): 1246 - 1255. [Abstract] [Full Text] [PDF]
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 S. Nakae, Y. Iwakura, H. Suto, and S. J. Galli Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17 J. Leukoc. Biol., May 1, 2007; 81(5): 1258 - 1268. [Abstract] [Full Text] [PDF]
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Y. Sun, S. E. Blink, W. Liu, Y. Lee, B. Chen, J. Solway, J. Weinstock, L. Chen, and Y.-X. Fu Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation J. Immunol., July 15, 2006; 177(2): 814 - 821. [Abstract] [Full Text] [PDF]
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J. Tong, H. S. Bandulwala, B. S. Clay, R. A. Anders, R. A. Shilling, D. D. Balachandran, B. Chen, J. V. Weinstock, J. Solway, K. J. Hamann, et al. Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma J. Exp. Med., May 15, 2006; 203(5): 1173 - 1184. [Abstract] [Full Text] [PDF]
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 D. Odobasic, A. R. Kitching, T. J. Semple, and S. R. Holdsworth Inducible Co-Stimulatory Molecule Ligand Is Protective during the Induction and Effector Phases of Crescentic Glomerulonephritis J. Am. Soc. Nephrol., April 1, 2006; 17(4): 1044 - 1053. [Abstract] [Full Text] [PDF]
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 V. M. Hubbard, J. M. Eng, T. Ramirez-Montagut, K. H. Tjoe, S. J. Muriglan, A. A. Kochman, T. H. Terwey, L. M. Willis, R. Schiro, G. Heller, et al. Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation Blood, November 1, 2005; 106(9): 3285 - 3292. [Abstract] [Full Text] [PDF]
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 B. R Blazar and W. J Murphy Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD) Phil Trans R Soc B, September 29, 2005; 360(1461): 1747 - 1767. [Abstract] [Full Text] [PDF]
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R. A. Shilling, J. M. Pinto, D. C. Decker, D. H. Schneider, H. S. Bandukwala, J. R. Schneider, B. Camoretti-Mercado, C. Ober, and A. I. Sperling Cutting Edge: Polymorphisms in the ICOS Promoter Region Are Associated with Allergic Sensitization and Th2 Cytokine Production J. Immunol., August 15, 2005; 175(4): 2061 - 2065. [Abstract] [Full Text] [PDF]
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B. U. Gajewska, A. Tafuri, F. K. Swirski, T. Walker, J. R. Johnson, T. Shea, A. Shahinian, S. Goncharova, T. W. Mak, M. R. Stampfli, et al. B7RP-1 Is Not Required for the Generation of Th2 Responses in a Model of Allergic Airway Inflammation but Is Essential for the Induction of Inhalation Tolerance J. Immunol., March 1, 2005; 174(5): 3000 - 3005. [Abstract] [Full Text] [PDF]
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L. Wassink, P. L. Vieira, H. H. Smits, G. A. Kingsbury, A. J. Coyle, M. L. Kapsenberg, and E. A. Wierenga ICOS Expression by Activated Human Th Cells Is Enhanced by IL-12 and IL-23: Increased ICOS Expression Enhances the Effector Function of Both Th1 and Th2 Cells J. Immunol., August 1, 2004; 173(3): 1779 - 1786. [Abstract] [Full Text] [PDF]
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 Y. P. de Jong, S. T. Rietdijk, W. A. Faubion, A. C. Abadia-Molina, K. Clarke, E. Mizoguchi, J. Tian, T. Delaney, S. Manning, J.-C. Gutierrez-Ramos, et al. Blocking inducible co-stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis Int. Immunol., February 1, 2004; 16(2): 205 - 213. [Abstract] [Full Text] [PDF]
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H.-S. Kang, S. E. Blink, R. K. Chin, Y. Lee, O. Kim, J. Weinstock, T. Waldschmidt, D. Conrad, B. Chen, J. Solway, et al. Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation J. Exp. Med., December 1, 2003; 198(11): 1643 - 1652. [Abstract] [Full Text] [PDF]
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 R. I. Nurieva, X. M. Mai, K. Forbush, M. J. Bevan, and C. Dong B7h is required for T cell activation, differentiation, and effector function PNAS, November 25, 2003; 100(24): 14163 - 14168. [Abstract] [Full Text] [PDF]
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 L. I. Rutitzky, E. Ozkaynak, J. B. Rottman, and M. J. Stadecker Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis Infect. Immun., July 1, 2003; 71(7): 4040 - 4044. [Abstract] [Full Text] [PDF]
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R. V. Parry, C. A. Rumbley, L. H. Vandenberghe, C. H. June, and J. L. Riley CD28 and Inducible Costimulatory Protein Src Homology 2 Binding Domains Show Distinct Regulation of Phosphatidylinositol 3-Kinase, Bcl-xL, and IL-2 Expression in Primary Human CD4 T Lymphocytes J. Immunol., July 1, 2003; 171(1): 166 - 174. [Abstract] [Full Text] [PDF]
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 R. E. Wiley, S. Goncharova, T. Shea, J. R. Johnson, A. J. Coyle, and M. Jordana Evaluation of Inducible Costimulator/B7-Related Protein-1 as a Therapeutic Target in a Murine Model of Allergic Airway Inflammation Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 722 - 730. [Abstract] [Full Text] [PDF]
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C. Mueller and A. August Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK J. Immunol., May 15, 2003; 170(10): 5056 - 5063. [Abstract] [Full Text] [PDF]
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K. M. Smith, J. M. Brewer, P. Webb, A. J. Coyle, C. Gutierrez-Ramos, and P. Garside Inducible Costimulatory Molecule-B7-Related Protein 1 Interactions Are Important for the Clonal Expansion and B Cell Helper Functions of Naive, Th1, and Th2 T Cells J. Immunol., March 1, 2003; 170(5): 2310 - 2315. [Abstract] [Full Text] [PDF]
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M. Lohning, A. Hutloff, T. Kallinich, H. W. Mages, K. Bonhagen, A. Radbruch, E. Hamelmann, and R. A. Kroczek Expression of ICOS In Vivo Defines CD4+ Effector T Cells with High Inflammatory Potential and a Strong Bias for Secretion of Interleukin 10 J. Exp. Med., January 20, 2003; 197(2): 181 - 193. [Abstract] [Full Text] [PDF]
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H.-W. Mittrucker, M. Kursar, A. Kohler, D. Yanagihara, S. K. Yoshinaga, and S. H. E. Kaufmann Inducible Costimulator Protein Controls the Protective T Cell Response Against Listeria monocytogenes J. Immunol., November 15, 2002; 169(10): 5813 - 5817. [Abstract] [Full Text] [PDF]
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M. J. Ekkens, Z. Liu, Q. Liu, A. Foster, J. Whitmire, J. Pesce, A. H. Sharpe, J. F. Urban, and W. C. Gause Memory Th2 Effector Cells Can Develop in the Absence of B7-1/B7-2, CD28 Interactions, and Effector Th Cells After Priming with an Intestinal Nematode Parasite J. Immunol., June 15, 2002; 168(12): 6344 - 6351. [Abstract] [Full Text] [PDF]
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R. J. Greenwald, A. J. McAdam, D. Van der Woude, A. R. Satoskar, and A. H. Sharpe Cutting Edge: Inducible Costimulator Protein Regulates Both Th1 and Th2 Responses to Cutaneous Leishmaniasis J. Immunol., February 1, 2002; 168(3): 991 - 995. [Abstract] [Full Text] [PDF]
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