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*
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115;
Department of Pathology, Harvard Medical School, Boston, MA 02115;
Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115;
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Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115;
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Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
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Department of Immunology, Genetics Institute, Cambridge, MA 02140
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-4, and IL-10, but not IL-2.
Second, TCR-transgenic CD4+ T cells were stimulated with
peptide and APC in the presence of ICOS-Ig or control Ig. When the
ICOS:B7h interaction was blocked by ICOS-Ig, CD4+ T cells
produced more IFN- and less IL-4 and IL-10 than CD4+
cells differentiated with control Ig. These results demonstrate that
ICOS stimulation is important in T cell activation and that ICOS may
have a particularly important role in development of Th2
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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,
TNF-
, and GM-CSF are also increased (1). The inducible expression of ICOS is especially interesting because it suggests that ICOS may be particularly important in costimulation of activated T cells. CD28 is expressed by most resting human T cells, and virtually all resting mouse T cells, whereas human ICOS is expressed after T cell activation (1, 2, 6, 7). Costimulation of CD28 appears to be key in the activation and differentiation of naive T cells early in the immune response (6, 8). The inducible expression of ICOS, together with preferential induction of IL-10 by ICOS stimulation, suggests that ICOS may amplify and/or regulate T cell responses.
Recently, a novel B7 family member (originally called B7h
(4) but also B7RP-1 (2), GL50
(9), and LICOS (10)), has been identified as
the ligand for ICOS (2, 3, 9, 10). B7h has 20% amino acid
identity with CD80 (B7-1) and CD86 (B7-2), which is similar to the
identity between CD80 and CD86. B7h has the necessary cysteines to form
extracellular IgV- and IgC-like domains, like CD80 and CD86
(4). As predicted from the lack of conservation of the
MYPPPY binding motif for CD80 and CD86, ICOS did not have detectable
binding to CD80 or CD86 (2, 9). B7h mRNA is expressed by a
variety of tissues, including spleen and unstimulated B cells, as well
as nonlymphoid tissues, and expression is up-regulated by TNF- and
LPS (4). ICOS-Ig fusion protein binds to freshly isolated
B cells and macrophages, suggesting that some APC constitutively
express B7h (2). However, ICOS ligand expression on
macrophages is increased by activation, and this induction is protein
kinase dependent (5). Dendritic cells from peripheral
blood do not bind to ICOS-Ig, but monocyte-derived dendritic cells do
express an ICOS ligand (2, 5).
The discovery of the ICOS-B7h pathway raises a number of questions
about the function of this pathway. To further characterize ICOS
expression and function, we have made anti-mouse-ICOS mAb and mouse
ICOS-Ig to assess the expression and function of ICOS during activation
and differentiation of mouse T cells. Our studies show that mouse T
cells express very little ICOS, ICOS expression is induced on the
surface of T cells after 24 h of stimulation with anti-CD3,
and CD28 stimulation is an important inducer of ICOS expression.
Further, we found that Th2 cell lines express significantly higher
levels of ICOS than do Th1 cell lines. To investigate the function of
ICOS in activation and differentiation of CD4+ T
cells, we have used ICOS-Ig and B7h-Ig. Stimulation of
CD4+ T cells with beads coated with anti-CD3
and B7h-Ig fusion protein increased proliferation and production of
IFN-, IL-4, and IL-10, but not IL-2. When differentiated in the
presence of ICOS-Ig, DO11.10 T cells produce substantially more IFN-
and less IL-4 and IL-10 than T cells differentiated in the presence of
control IgG2a.
Taken together, our studies demonstrate that ICOS can stimulate both Th1 and Th2 cytokine production, but may have a preferential role in the generation of Th2 cells. Our data also indicate that B7 costimulation may be needed to optimally induce ICOS expression, suggesting that some of the functions ascribed to the CD28 pathway may be mediated through ICOS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A search of the mouse expressed sequence tag database for
sequences with homology to CD28 identified AI006009. This expressed
sequence tag was sequenced and found to be the mouse orthologue of
human ICOS with 69% amino acid identity. The extracellular domain
contains a single IgV-like domain. Like CD28 and CTLA-4, ICOS contains
an extra pair of cysteines in the IgV domain, a membrane-proximal
cysteine that mediates dimerization of the protein, and a
phosphatidylinositol-3 kinase signaling motif in the cytoplasmic tail.
The mouse ICOS protein sequence is identical with that recently
described by Yoshinaga et al. (2). The mouse ICOS cDNA was
excised by EcoRI/NotI digestion and subcloned
into the pcDNA3.1 (Invitrogen, San Diego, CA) mammalian expression
vector. A hemagglutinin (HA)-epitope-tagged mouse ICOS was generated by
cloning a PCR fragment consisting of the IgV transmembrane and
cytoplamic domains downstream of the IgK signal and HA epitope domains
in the pDisplay vector (Invitrogen). Jurkat cells were transfected with
mouse HA-ICOS in pDisplay, selected with G418, sorted twice for
expression using the anti-HA mAb, 12CA5 (Boehringer Mannheim,
Indianapolis, IN), and subcloned. A soluble, hexahistidine-tagged form
of mouse ICOS was generated by cloning the IgV domain into the
pPICZB vector, followed by transformation into Pichia
pastoris. Protein was induced according to the manufacturer’s
instructions (Invitrogen) and purified to homogeneity on Nickel-NTA and
Mono-Q columns. Chinese hamster ovary (CHO) cells were transfected with
mouse ICOS cDWA in pCDNA3.1, selected with G418, sorted twice using
flow cytometry for mouse ICOS expression using anti-ICOS polyclonal
anti-serum, and subcloned.
Preparation of mAbs to ICOS
Rats were immunized i.m. three times with 500 µg ICOS cDNA in the pAXEF mammalian expression vector and boosted twice with 200 µg ICOS hexahistidine fusion protein. Spleen cells were fused with SP2/0 myeloma cells and cloned, and the hybridomas were screened by ELISA for reactivity with ICOS hexahistidine fusion protein and by flow cytometry with HA-ICOS-Jurkat cell transfectants. Positive hybridomas were further screened on ICOS-transfected COS or CHO cells. Ten anti-ICOS-specific hybridomas were made. mAb from clone 7E.17G9 (rat IgG2b) was purified and conjugated to FITC using standard techniques.
Animals
BALB/c mice were bought from Taconic Farms (Germantown, NY). BALB/c mice expressing a transgene for the DO11.10 TCR (DO11 mice; Ref. 11), specific for amino acids 323–329 of OVA (OVA peptide) and I-Ad, wild-type 129/SvS4Jae and 129/SvS4Jae mice lacking CD80 and CD86 (B7-1/2-/-; Ref. 12) were bred in our facility. All mice were 6–8 wk old. Brigham and Women’s Hospital is accredited by the American Association of Accreditation of Laboratory Animal Care and mice were cared for in accordance with institutional guidelines in a pathogen-free facility.
Analysis of ICOS expression
For measurement of ICOS expression on freshly isolated cells the thymus, spleen, Peyer’s patches, peripheral lymph nodes (pooled axillary and inguinal), and mesenteric lymph nodes were obtained from BALB/c mice. Thymocytes were triple stained for ICOS (FITC), CD4 (Cy-Chrome), and CD8 (PE). Lymphocytes of the other tissues were double stained for ICOS (FITC) and either CD4 or CD8 (PE). Except for anti-ICOS, all Abs used for flow cytometry were from PharMingen (San Diego, CA). Staining and analysis were completed as previously described (13).
To determine ICOS expression on Th1 and Th2 cells, CD4+ cells from DO11 mice were purified by magnetic cell separation system (Miltenyi Biotec, Auburn, CA), according to the manufacturer’s instructions. A total of 2 x 105 CD4+ cells were stimulated with 3 x 106 mitomycin-C-inactivated APC and 1 µg/ml OVA peptide. Cultures of Th1 cells were initiated by adding 1 µg/ml anti-IL-4 (11B11, from American Type Culture Collection, Manassas, VA) and 10 ng/ml IL-12 (prepared at Genetics Institute, Cambridge, MA), and Th2 cells were initiated by adding 1000 U/ml IL-4 (from PharMingen) to DO11.10 CD4+ cells stimulated with peptide and APC. T cells were restimulated every 7 days with the same level of APC and peptide as in the primary stimulation. Differentiating factors (IL-4, IL-12, and anti-IL-4) were used at half the initial concentration for each stimulation after the primary. Four days after each restimulation, Th lines were stained for ICOS expression with anti-ICOS-FITC (or with control rIg-FITC) and the transgenic TCR (biotin-conjugated KJ126 Ab followed by avidin-PE). The data were analyzed by measuring fluorescence of ICOS (or rIg control) after gating on forward scatter and side scatter for activated lymphocytes and on D011.10 TCR expression. ICOS-specific fluorescence was calculated by subtracting the fluorescence with rIg-FITC from the fluorescence of anti-ICOS-FITC. The fluorescence with rIg-FITC was always low (range 2.7–5.7). To confirm differentiation of Th1 and Th2, the cell lines were also stimulated each week with APC and peptide without differentiating factors; 2 days after stimulation, the supernatants of these cultures were collected for cytokine analysis by ELISA.
The effect of CD3 and CD28 stimulation on ICOS expression was determined by incubating splenocytes from 129/SvS4Jae mice (wild type or B7-1/2-/-) with no Ab (unstimulated control), anti-CD3 (1 µg/ml 145-2C11, prepared by Bioexpress, West Lebanon, NH), anti-CD28 (a 1/1000 dilution of a concentrated preparation of 37.51), or both anti-CD3 and anti-CD28. Twenty-four hours later, cells were stained with anti-ICOS-FITC and CD4-PE or CD8-PE.
The role of ICOS in Th differentiation
Two systems were used to investigate the role of ICOS in proliferation and differentiation of CD4+ cells. First, purified CD4+ cells were stimulated with beads coated with anti-CD3 and either B7h-Ig or control fusion protein. Second, purified CD4+ cells from TCR-transgenic mice were stimulated with cognate peptide and APC, in the presence of either ICOS-Ig (9) or control IgG2a.
Latex beads (Interfacial Dynamics Corporation, Portland, OR) were
resuspended in PBS at 107 beads/ml. Purified
anti-CD3 (1 µg/ml) and either B7h-Ig (prepared at Genetics
Institute) or control fusion protein (each at 3 µg/ml) were added and
conjugated to the beads for 2 h at 37 C. The B7h-Ig was purified
from CHO cells and consists of the extracellular domains of mouse B7h
fused to the Fc domain of mouse IgG2a. B7h-Ig binds to COS cells
transfected with mouse ICOS, but not to control COS transfectants. The
beads were extensively washed and then incubated with RPMI 1640 with
10% FCS for 1 h at 37 C. CD4+ cells were
purified from BALB/c mice by magnetic cell sorting system (Miltenyi
Biotec). A total of 105 purified
CD4+ cells were stimulated in 96-well
round-bottom plates with beads ranging from 690 to 5 x
105/well (or no beads as a control).
[3H]Thymidine was added for the last 6 h
of a 3-day culture to determine proliferation. To determine the effect
of ICOS stimulation on cytokine production, supernatants were collected
from CD4+ cells stimulated as above with 1.7
x 105 beads. Supernatants were collected on day
3 for measurement of IL-2, IL-4, and IFN-, and day 4 for IL-10.
Cytokines were measured by ELISA as previously described
(14).
To evaluate the effects of ICOS on the differentiation of naive T cells
during stimulation with splenic APC, CD4+ cells
were purified from naive DO11 mice. A total of 2 x
105 CD4+ cells were
stimulated with 3 x 106
mitomycin-c-inactivated APC and 1 µg/ml OVA peptide, with 10 µg/ml
of either ICOS-IgG2a fusion protein or control mouse IgG2a. ICOS-Ig
fusion protein has previously been shown to bind to B7h/GL50
(9). Five days later, the cells were harvested and
restimulated with APC and OVA peptide as described above. Supernatants
were collected from the first 3 days of the primary and secondary
cultures and tested for IL-2, IL-4, IL-10, and IFN- by ELISA as
previously described (14).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We made anti-mouse ICOS-specific mAbs to characterize mouse
ICOS expression. Anti-mouse ICOS specificity was confirmed by
reactivity with ICOS-transfected CHO and COS cells and lack of
reactivity with vector-transfected cells (Fig. 1
A and data not shown). The
7E.17G9 Ab blocks binding between ICOS and B7h (data not shown).
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B). This level of expression is
significantly higher than that of resting peripheral lymphocytes
(compare with Fig. 1C). Thymic
CD4+8+ and
CD4-8+ cells do not show
appreciable staining with anti-ICOS. Expression of ICOS on
thymocyte subpopulations raises the possibility that ICOS may be
involved in thymic selection.
Freshly isolated cells from peripheral lymphoid tissues were also
analyzed for ICOS expression. The T cells from the spleen, peripheral
lymph nodes (pooled axillary and inguinal nodes), and mesenteric lymph
nodes express a low level of ICOS (Fig. 1C). A total
of 17% of CD4+ cells in the Peyer’s patches
express a higher level of ICOS, although Peyer’s patches
CD8+ cells express only a low level. Expression
of ICOS by the Peyer’s patch CD4+ cells may
reflect activation of these T cells.
To investigate the regulation of ICOS expression, we stimulated whole
splenocytes from wild-type or B7-1/2-/- mice
with anti-CD3, anti-CD28, both, or neither for 24 h.
Expression of ICOS on unstimulated T lymphocytes was similar to the
very low level on freshly isolated splenocytes. Stimulation of
wild-type splenocytes with anti-CD3 for 24 h induced
expression of a high level of ICOS on nearly all of the
CD4+ and CD8+ cells (Fig. 2). After 48 or 72 h, levels of ICOS
were lower than at 24 h, although still higher than on resting
cells (data not shown). Interestingly, anti-CD3 stimulation was
less effective at inducing ICOS expression in cultures lacking CD80 and
CD86 (Fig. 2). The level of ICOS induced in the wild-type culture is
8-fold higher than that in the culture lacking CD80 and CD86. This
suggested that expression of ICOS might be partially dependent on CD28
costimulation. Indeed, addition of anti-CD28 to anti-CD3
stimulated B7-1/2-/- splenocytes increased ICOS
expression on CD4+ and CD8+
cells to levels similar to that on anti-CD3 stimulated cells from
wild-type splenocytes (Fig. 2). Addition of anti-CD28 alone
(without anti-CD3) did not up-regulate ICOS expression by T cells
in wild-type or B7-1/2-/- cultures (data not
shown).
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Because human ICOS has been implicated in cytokine production
(1), we investigated the ICOS expression during
differentiation of Th1 and Th2 cell lines. CD4+
DO11-transgenic T cells were stimulated with OVA peptide under Th1 or
Th2 differentiating conditions every 7 days for 9 wk. Four days after
each stimulation, cells were stained and analyzed for ICOS expression.
In addition, each week the Th1 and Th2 cell lines were stimulated with
OVA peptide and APC without differentiating agents to determine the
extent of the differentiation to Th1 or Th2. Supernatant from T cells
deviated toward Th1 contained IFN- (mean, >25 ng/ml) and IL-2
(mean, 0.93 ng/ml), but no detectable IL-4 or IL-10 (<0.1 ng/ml).
Supernatants from Th2-deviated cells contained IL-4 (mean, 4.1 ng/ml)
and IL-10 (mean, 5.1 ng/ml), but little IFN- (mean, 0.23 ng/ml) and
no detectable IL-2 (<0.1 ng/ml), indicating that our differentiation
protocol was effective.
Expression of ICOS was very low on the freshly isolated TCR-transgenic
T cells (Fig. 3A). After
primary stimulation, Th1 and Th2 cells expressed comparably high levels
of ICOS. At each subsequent time tested, the Th2
D011.10+ cells continued to express high levels
of ICOS (ICOS-specific fluorescence of Th2 ranged from 81 to 135, which
is less than 2-fold variation). In contrast, the ICOS expression on the
Th1 cell line decreased over time. Th1 cells consistently expressed a
low level of ICOS during weeks 5–9. Despite being at a significantly
lower level than on the Th2, ICOS was detectable on the Th1 throughout
the experiment (Fig. 3B). To determine whether the level of
ICOS on differentiated Th1 and Th2 varied with the time after
restimulation, we tested ICOS expression 1, 2, 4, and 6 days after
stimulation during the fifth week of culture. On all days, ICOS was
lower on Th1 than Th2.
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To evaluate the role of ICOS in T cell stimulation, we first used a simplified system, stimulating purified CD4+ cells with latex beads coated with anti-CD3 and either B7h-Ig or control fusion protein. This allows determination of the effects of ICOS costimulation in the absence of costimulation or other signals from APC.
Stimulation of CD4+ T cells with anti-CD3 and
B7h-Ig increased both proliferation and cytokine production by
CD4+ T cells compared with anti-CD3 and
control Ig (Fig. 4). Between 6.2 x
103 and 1.7 x 105
beads per well, anti-CD3/B7h-coated beads elicited 1.5- to 1.9-fold
more proliferation than did anti-CD3/control Ig-coated beads (Fig. 4A). At the highest concentrations of beads, the effect of
anti-CD3 reached a plateau, so that at 5 x
105 beads per well, proliferation was similar in
cells stimulated with the two types of beads. B7h on the beads did not
significantly affect production of IL-2 (Fig. 4B). This was
true over a range of bead concentrations (as in Fig. 4A) at
days 1–4 (Fig. 4B and data not shown). However, B7h
costimulation increased production of IFN-, IL-4, and IL-10 by 7.5-,
3.2-, and 3.7-fold, respectively (Fig. 4B). These data
demonstrate that ICOS costimulation can enhance proliferation of
CD4+ T cells. Further, both Th1 and Th2 cytokines
are enhanced by ICOS costimulation.
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ICOS ligand is expressed by a variety of cells, including most B cells and macrophages in freshly isolated splenocytes (2). Because B7h is expressed by resting APC, we decided to manipulate the ICOS pathway by blocking the interaction of B7h and ICOS during primary T cell stimulation using an ICOS-Ig fusion protein. This protein binds to B7h (9), and so would be expected to block the interaction of ICOS with ICOS ligand.
We used CD4+ T cells from DO11 TCR-transgenic mice (11) to evaluate the role of ICOS costimulation in CD4+ T cell activation and differentiation. The use of TCR-transgenic T cells has several advantages for the study of CD4+ T cell differentiation. First, the majority of the T cells are naive. Second, T cells are of known antigenic specificity, so they can be stimulated with physiologic signals (peptide and MHC on APC).
We have previously identified conditions under which naive DO11
TCR-transgenic T cells produce IL-2, IFN-, and IL-4 upon
restimulation with APCs and OVA peptide (14, 15). To
determine whether ICOS influences T cell differentiation, we used these
conditions to prime naive DO11 T cells with APCs and OVA peptide in the
presence of ICOS-Ig or control mouse IgG2a. After 5 days, the T cells
were restimulated with OVA peptide and APC for 3 days. Proliferation
and cytokine production were measured during the first 3 days of each
culture.
ICOS-Ig did not significantly alter proliferation in the primary or
secondary stimulations (Fig. 5). However,
the addition of ICOS-Ig during primary stimulation dramatically skewed
Th differentiation. There was increased production of the Th1 cytokine
IFN- and decreased production of the Th2 cytokines IL-4 and IL-10
upon secondary stimulation (Fig. 6). In
the primary culture, the presence of ICOS-Ig increased production of
IFN- on day 3 by 3-fold. ICOS-Ig did not significantly alter
production of IL-2 in the primary culture. IL-4 and IL-10 were not
detectable in primary culture supernatants. Production of cytokines in
secondary culture was profoundly affected by ICOS-Ig in the primary
culture. Production of IFN- was increased by the addition of ICOS-Ig
by 7-fold on days 2 and 3, respectively. IL-2 was not detectable in
supernatants from secondary cultures. The addition of ICOS-Ig decreased
production of IL-4 to 25 and 4% of control levels on days 2 and 3,
respectively. IL-10 production was decreased to 20 and 7% of control
levels on days 2 and 3 of the secondary culture.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-4, and IL-10, but not
IL-2; and ICOS blockade decreases Th2 differentiation. Taken together,
these studies demonstrate that ICOS stimulates both Th1 and Th2
cytokine production but may have a preferential role in Th2 cell
development. Our studies also suggest a functionally significant
interaction between CD28 and ICOS pathways. In particular, our data
suggest that CD80/CD86 costimulation may be needed to optimally
up-regulate ICOS expression and that the CD28 pathway may exert some of
its effects (such as Th2 differentiation) via ICOS. In the two major costimulatory pathways for the initial activation of lymphocytes, CD28-CD80/CD86 and CD40-CD40 ligand (CD40L), the signaling molecule (CD28 or CD40) is constitutively expressed and the counterreceptor is inducible (CD80, CD86, and CD40L; Ref. 6). In contrast, in the B7h/ICOS pathway, the putative signaling molecule, ICOS, is induced after activation (Ref. 1 and this report). The ICOS counter receptor is constitutively expressed by B cells and macrophages (2, 5), although it can be further induced by activation of macrophages (5). Therefore, stimulation of T cells through ICOS will depend primarily on induction of ICOS, which can then interact with the constitutively expressed ligand. Determining the factors that regulate ICOS induction may be key to understanding when this pathway is important.
We have found that costimulation of CD28 by CD80 or CD86 enhanced
expression of ICOS, although ICOS could be induced in the absence of
CD80 and CD86 (Fig. 2). This enhancement of ICOS expression by CD28 is
similar to CD28 mediated enhancement of IL-2R and CD40L expression; a
CD3 signal alone can induce expression, but CD28 costimulation
increases and prolongs expression (16, 17). However, the
ICOS pathway appears to preferentially promote Th2 development, whereas
CD40L-CD40 interaction can enhance generation of a Th1 response by
increasing IL-12 production (18). Human
CD4+ cells express higher levels of ICOS than do
human CD8+ cells (1). Similarly,
after activation with anti-CD3, mouse CD8+
cells expressed slightly less ICOS than do CD4+
cells (Fig. 2). The level and percent of mouse T cells expressing ICOS
appears to be higher than that on human T cells (Fig. 3 and Ref.
1). This may reflect actual differences in the level of
ICOS expressed by human and mouse cells, or differences in the staining
reagents or activation conditions.
Our results indicate that ICOS stimulation has a modest effect on
proliferation. Consistent with this, there was no detectable effect of
ICOS blockade or ICOS stimulation by B7h on IL-2 production (Figs. 4 and 6, and Ref. 1). ICOS-Ig did not block proliferation of
CD4+ cells stimulated with peptide and APC (Figs. 5 and 6). Conversely, B7h-Ig costimulation modestly increased
proliferation of CD4+ cells stimulated with
anti-CD3-coated beads (1.5- to 1.9-fold, Fig. 4). Stimulation of
the purified CD4+ cells with
anti-CD3-conjugated beads is an APC-free system in which the B7h is
the primary source of costimulation. In contrast, when APC are
present during the stimulation of the DO11.10 TCR-transgenic T cells,
the modest effect of ICOS stimulation on proliferation may be obscured
by the presence of other costimulatory molecules. Consistent with the
modest effect of ICOS stimulation on proliferation of
CD4+ cells, it has been demonstrated that
allo-reactive or secondary proliferation of human T cells are better
inhibited by blocking the CD28 pathway than by blocking the ICOS
pathway (5).
ICOS stimulation had marked effects on cytokine production. When
purified CD4+ cells were stimulated with
anti-CD3 and B7h-Ig-coated beads, production of IL-4, IL-10, and
IFN- were enhanced, whereas production of IL-2 was not affected
(Fig. 4). Moreover, blocking the ICOS pathway with ICOS-Ig skewed
differentiation of DO11.10 TCR-transgenic cells from Th2 and toward Th1
with high IFN- production (Fig. 6). How can the apparent discrepancy
in IFN- production be reconciled? Multiple pathways, including
IL-12, CD80/CD86, signaling lymphocytic activation molecule, and DNAX
accessory molecule-1 can enhance production of IFN- (6, 19, 20, 21). These may stimulate IFN- production whether ICOS is
blocked with ICOS-Ig. Because IL-4 and IL-10 antagonize IFN-
production, the strong inhibition of IL-4 and IL-10 production by
ICOS-Ig may allow these other pathways to more strongly stimulate
IFN- production. IL-4 production is largely dependent on
costimulation through CD28 (6, 15, 22, 23), and we have
shown here that ICOS costimulation can also enhance IL-4 production.
Because induction of ICOS is partially dependent on CD28 costimulation
(Fig. 2), it may be that the ability of CD28 stimulation to enhance
IL-4 production is mediated through up-regulation of ICOS. Together,
these results show that, whereas ICOS stimulation can enhance both Th1
and Th2 cytokines, ICOS may be particularly important in Th2
generation. It is also possible that the changes in cytokine production
may be due to ICOS stimulation of other T cell subsets, such as
T-regulatory 1 cells, which produce high levels of IL-10
(24). However, T-regulatory 1 cells do not produce IL-4,
so we favor the hypothesis that ICOS stimulation contributes to Th2
generation (25).
The effects of ICOS blockade correlate with the higher level of ICOS expression on Th2 compared with Th1 cells. Immediately after activation of CD4+ cells under conditions to generate Th1 or Th2, both populations express high levels of ICOS. When the supernatants from cells restimulated after this first cycle of stimulation were tested for cytokines, it was evident that they had already differentiated into Th1 and Th2, so differentiation into Th1 and Th2 precedes the difference in ICOS expression. After secondary stimulation, ICOS expression declines on Th1 cells but remains high on Th2 cells. The pattern of ICOS expression is in contrast to SLAM expression. SLAM is expressed at higher levels by Th1 than Th2 (20). It will be interesting to determine what signals or cytokines regulate ICOS expression in these populations.
The demonstration that ICOS stimulation may enhance Th2 development suggests that the ICOS pathway may be a good target for immunotherapy in a variety of immune-mediated diseases. Blocking reagents, such as the ICOS-Ig used in this report, have significant potential to reduce the development of harmful Th2 responses, such as those seen in allergic responses (26). Alternatively, stimulation of the ICOS pathway might shift undesirable Th1 responses in graft rejection and autoimmunity toward Th2 responses (26). Manipulation of ICOS may have the potential to affect responses of naive or effector T cells. Our results give impetus to further studies to determine whether manipulation of the ICOS pathway in vivo can alter the outcome of the immune response.
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Footnotes |
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2 A.J.M. and T.T.C. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Gordon Freeman, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115.
4 Abbreviations used in this paper: ICOS, inducible costimulatory; OVA peptide, amino acids 323–329 of OVA; B7-1/2-/- mice, mice lacking CD80 and CD86; HA, hemagglutinin; CHO, Chinese hamster ovary; CD40L, CD40 ligand.
Received for publication June 26, 2000. Accepted for publication August 10, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Immunity 11:423.[Medline]
mRNA stability by IL-12/NKSF. Cell. Immunol. 159:140.[Medline]
production. J. Exp. Med. 179:299.This article has been cited by other articles:
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H. Lu, B. L. F. Kaplan, T. Ngaotepprutaram, and N. E. Kaminski Suppression of T cell costimulator ICOS by {Delta}9-tetrahydrocannabinol J. Leukoc. Biol., February 1, 2009; 85(2): 322 - 329. [Abstract] [Full Text] [PDF]
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 B. Peng, P. Ye, B. R. Blazar, G. J. Freeman, D. J. Rawlings, H. D. Ochs, and C. H. Miao Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice Blood, September 1, 2008; 112(5): 1662 - 1672. [Abstract] [Full Text] [PDF]
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C. Fos, A. Salles, V. Lang, F. Carrette, S. Audebert, S. Pastor, M. Ghiotto, D. Olive, G. Bismuth, and J. A. Nunes ICOS Ligation Recruits the p50{alpha} PI3K Regulatory Subunit to the Immunological Synapse J. Immunol., August 1, 2008; 181(3): 1969 - 1977. [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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O. Akbari, P. Stock, E. H. Meyer, G. J. Freeman, A. H. Sharpe, D. T. Umetsu, and R. H. DeKruyff ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival J. Immunol., April 15, 2008; 180(8): 5448 - 5456. [Abstract] [Full Text] [PDF]
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 J. M. Rojo, E. Pini, G. Ojeda, R. Bello, C. Dong, R. A. Flavell, U. Dianzani, and P. Portoles CD4+ICOS+ T lymphocytes inhibit T cell activation 'in vitro' and attenuate autoimmune encephalitis 'in vivo' Int. Immunol., April 1, 2008; 20(4): 577 - 589. [Abstract] [Full Text] [PDF]
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C. Wiethe, A. Debus, M. Mohrs, A. Steinkasserer, M. Lutz, and A. Gessner Dendritic Cell Differentiation State and Their Interaction with NKT Cells Determine Th1/Th2 Differentiation in the Murine Model of Leishmania major Infection J. Immunol., April 1, 2008; 180(7): 4371 - 4381. [Abstract] [Full Text] [PDF]
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F.-X. Hubert, S. A. Kinkel, K. E. Webster, P. Cannon, P. E. Crewther, A. I. Proeitto, L. Wu, W. R. Heath, and H. S. Scott A Specific Anti-Aire Antibody Reveals Aire Expression Is Restricted to Medullary Thymic Epithelial Cells and Not Expressed in Periphery J. Immunol., March 15, 2008; 180(6): 3824 - 3832. [Abstract] [Full Text] [PDF]
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F. Vu, U. Dianzani, C. F. Ware, T. Mak, and J. L. Gommerman ICOS, CD40, and Lymphotoxin {beta} Receptors Signal Sequentially and Interdependently to Initiate a Germinal Center Reaction J. Immunol., February 15, 2008; 180(4): 2284 - 2293. [Abstract] [Full Text] [PDF]
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 A. H.-M. Tan, S. Y.-P. Goh, S.-C. Wong, and K.-P. Lam T Helper Cell-specific Regulation of Inducible Costimulator Expression via Distinct Mechanisms Mediated by T-bet and GATA-3 J. Biol. Chem., January 4, 2008; 283(1): 128 - 136. [Abstract] [Full Text] [PDF]
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T. L. Papenfuss, A. P. Kithcart, N. D. Powell, M. A. McClain, I. E. Gienapp, T. M. Shawler, and C. C. Whitacre Disease-modifying capability of murine Flt3-ligand DCs in experimental autoimmune encephalomyelitis J. Leukoc. Biol., December 1, 2007; 82(6): 1510 - 1518. [Abstract] [Full Text] [PDF]
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I. J. Thomas, L. G. Petrich de Marquesini, R. Ravanan, R. M. Smith, S. Guerder, R. A. Flavell, D. C. Wraith, L. Wen, and F. S. Wong CD86 Has Sustained Costimulatory Effects on CD8 T Cells J. Immunol., November 1, 2007; 179(9): 5936 - 5946. [Abstract] [Full Text] [PDF]
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 E. Marks, M. Verolin, A. Stensson, and N. Lycke Differential CD28 and Inducible Costimulatory Molecule Signaling Requirements for Protective CD4+ T-Cell-Mediated Immunity against Genital Tract Chlamydia trachomatis Infection Infect. Immun., September 1, 2007; 75(9): 4638 - 4647. [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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 C. L. Van Hove, T. Maes, G. F. Joos, and K. G. Tournoy Prolonged Inhaled Allergen Exposure Can Induce Persistent Tolerance Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 573 - 584. [Abstract] [Full Text] [PDF]
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K. C. Beier, T. Kallinich, and E. Hamelmann Master switches of T-cell activation and differentiation Eur. Respir. J., April 1, 2007; 29(4): 804 - 812. [Abstract] [Full Text] [PDF]
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 I. Gotsman, N. Grabie, R. Gupta, R. Dacosta, M. MacConmara, J. Lederer, G. Sukhova, J. L. Witztum, A. H. Sharpe, and A. H. Lichtman Impaired Regulatory T-Cell Response and Enhanced Atherosclerosis in the Absence of Inducible Costimulatory Molecule Circulation, November 7, 2006; 114(19): 2047 - 2055. [Abstract] [Full Text] [PDF]
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A. H.-M. Tan, S.-C. Wong, and K.-P. Lam Regulation of Mouse Inducible Costimulator (ICOS) Expression by Fyn-NFATc2 and ERK Signaling in T Cells J. Biol. Chem., September 29, 2006; 281(39): 28666 - 28678. [Abstract] [Full Text] [PDF]
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E. C. Logue, S. Bakkour, M. M. Murphy, H. Nolla, and W. C. Sha ICOS-Induced B7h Shedding on B Cells Is Inhibited by TLR7/8 and TLR9 J. Immunol., August 15, 2006; 177(4): 2356 - 2364. [Abstract] [Full Text] [PDF]
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E. H. Wilson, C. Zaph, M. Mohrs, A. Welcher, J. Siu, D. Artis, and C. A. Hunter B7RP-1-ICOS Interactions Are Required for Optimal Infection-Induced Expansion of CD4+ Th1 and Th2 Responses J. Immunol., August 15, 2006; 177(4): 2365 - 2372. [Abstract] [Full Text] [PDF]
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R. Watanabe, Y. Harada, K. Takeda, J. Takahashi, K. Ohnuki, S. Ogawa, D. Ohgai, N. Kaibara, O. Koiwai, K. Tanabe, et al. Grb2 and Gads Exhibit Different Interactions with CD28 and Play Distinct Roles in CD28-Mediated Costimulation J. Immunol., July 15, 2006; 177(2): 1085 - 1091. [Abstract] [Full Text] [PDF]
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B. Knoechel, J. Lohr, S. Zhu, L. Wong, D. Hu, L. Ausubel, and A. K. Abbas Functional and Molecular Comparison of Anergic and Regulatory T Lymphocytes. J. Immunol., June 1, 2006; 176(11): 6473 - 6483. [Abstract] [Full Text] [PDF]
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M. F. Quiroga, V. Pasquinelli, G. J. Martinez, J. O. Jurado, L. C. Zorrilla, R. M. Musella, E. Abbate, P. A. Sieling, and V. E. Garcia Inducible Costimulator: A Modulator of IFN-{gamma} Production in Human Tuberculosis J. Immunol., May 15, 2006; 176(10): 5965 - 5974. [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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 S. A. Nanji, W. W. Hancock, B. Luo, C. D. Schur, R. L. Pawlick, L. F. Zhu, C. C. Anderson, and A.M. J. Shapiro Costimulation Blockade of Both Inducible Costimulator and CD40 Ligand Induces Dominant Tolerance to Islet Allografts and Prevents Spontaneous Autoimmune Diabetes in the NOD Mouse Diabetes, January 1, 2006; 55(1): 27 - 33. [Abstract] [Full Text] [PDF]
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G. C. Zeller, J. Hirahashi, A. Schwarting, A. H. Sharpe, and V. R. Kelley Inducible Co-Stimulator Null MRL-Faslpr Mice: Uncoupling of Autoantibodies and T Cell Responses in Lupus J. Am. Soc. Nephrol., January 1, 2006; 17(1): 122 - 130. [Abstract] [Full Text] [PDF]
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M. Vidric, W.-K. Suh, U. Dianzani, T. W. Mak, and T. H. Watts Cooperation between 4-1BB and ICOS in the Immune Response to Influenza Virus Revealed by Studies of CD28/ICOS-Deficient Mice J. Immunol., December 1, 2005; 175(11): 7288 - 7296. [Abstract] [Full Text] [PDF]
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K. Miyamoto, C. I. Kingsley, X. Zhang, C. Jabs, L. Izikson, R. A. Sobel, H. L. Weiner, V. K. Kuchroo, and A. H. Sharpe The ICOS Molecule Plays a Crucial Role in the Development of Mucosal Tolerance J. Immunol., December 1, 2005; 175(11): 7341 - 7347. [Abstract] [Full Text] [PDF]
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P. H. Tan, J. B. Yates, S.-A. Xue, C. Chan, W. J. Jordan, J. E. Harper, M. P. Watson, R. Dong, M. A. Ritter, R. I. Lechler, et al. Creation of tolerogenic human dendritic cells via intracellular CTLA4: a novel strategy with potential in clinical immunosuppression Blood, November 1, 2005; 106(9): 2936 - 2943. [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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J. Kim, A. C. Myers, L. Chen, D. M. Pardoll, Q.-A. Truong-Tran, A. P. Lane, J. F. McDyer, L. Fortuno, and R. P. Schleimer Constitutive and Inducible Expression of B7 Family of Ligands by Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., September 1, 2005; 33(3): 280 - 289. [Abstract] [Full Text] [PDF]
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 H. Tamura, K. Dan, K. Tamada, K. Nakamura, Y. Shioi, H. Hyodo, S.-D. Wang, H. Dong, L. Chen, and K. Ogata Expression of Functional B7-H2 and B7.2 Costimulatory Molecules and Their Prognostic Implications in De novo Acute Myeloid Leukemia Clin. Cancer Res., August 15, 2005; 11(16): 5708 - 5717. [Abstract] [Full Text] [PDF]
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 M. G. Petroff, E. Kharatyan, D. S. Torry, and L. Holets The Immunomodulatory Proteins B7-DC, B7-H2, and B7-H3 Are Differentially Expressed across Gestation in the Human Placenta Am. J. Pathol., August 1, 2005; 167(2): 465 - 473. [Abstract] [Full Text] [PDF]
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V. Dardalhon, A. S. Schubart, J. Reddy, J. H. Meyers, L. Monney, C. A. Sabatos, R. Ahuja, K. Nguyen, G. J. Freeman, E. A. Greenfield, et al. CD226 Is Specifically Expressed on the Surface of Th1 Cells and Regulates Their Expansion and Effector Functions J. Immunol., August 1, 2005; 175(3): 1558 - 1565. [Abstract] [Full Text] [PDF]
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M. E. A. T. van Berkel, E. H. R. Schrijver, F. M. A. Hofhuis, A. H. Sharpe, A. J. Coyle, C. P. Broeren, K. Tesselaar, and M. A. Oosterwegel ICOS Contributes to T Cell Expansion in CTLA-4 Deficient Mice J. Immunol., July 1, 2005; 175(1): 182 - 188. [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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Y. Zheng, M. Jost, J. P. Gaughan, R. Class, A. J. Coyle, and M. Monestier ICOS-B7 Homologous Protein Interactions Are Necessary for Mercury-Induced Autoimmunity J. Immunol., March 1, 2005; 174(5): 3117 - 3121. [Abstract] [Full Text] [PDF]
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M. Watanabe, S. Watanabe, Y. Hara, Y. Harada, M. Kubo, K. Tanabe, H. Toma, and R. Abe ICOS-Mediated Costimulation on Th2 Differentiation Is Achieved by the Enhancement of IL-4 Receptor-Mediated Signaling J. Immunol., February 15, 2005; 174(4): 1989 - 1996. [Abstract] [Full Text] [PDF]
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C. M. Krawczyk, R. G. Jones, A. Atfield, K. Bachmaier, S. Arya, B. Odermatt, P. S. Ohashi, and J. M. Penninger Differential Control of CD28-Regulated In Vivo Immunity by the E3 Ligase Cbl-b J. Immunol., February 1, 2005; 174(3): 1472 - 1478. [Abstract] [Full Text] [PDF]
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Y. Bian, S.-i. Hiraoka, M. Tomura, X.-Y. Zhou, Y. Yashiro-Ohtani, Y. Mori, J. Shimizu, S. Ono, K. Dunussi-Joannopoulos, S. Wolf, et al. The capacity of the natural ligands for CD28 to drive IL-4 expression in naive and antigen-primed CD4+ and CD8+ T cells Int. Immunol., January 1, 2005; 17(1): 73 - 83. [Abstract] [Full Text] [PDF]
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D. Yadav, V. Judkowski, M. Flodstrom-Tullberg, L. Sterling, W. L. Redmond, L. Sherman, and N. Sarvetnick B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets J. Immunol., September 15, 2004; 173(6): 3631 - 3639. [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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B. Greve, L. Vijayakrishnan, A. Kubal, R. A. Sobel, L. B. Peterson, L. S. Wicker, and V. K. Kuchroo The Diabetes Susceptibility Locus Idd5.1 on Mouse Chromosome 1 Regulates ICOS Expression and Modulates Murine Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2004; 173(1): 157 - 163. [Abstract] [Full Text] [PDF]
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C. Hausl, R. U. Ahmad, H. P. Schwarz, E. M. Muchitsch, P. L. Turecek, F. Dorner, and B. M. Reipert Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders Blood, July 1, 2004; 104(1): 115 - 122. [Abstract] [Full Text] [PDF]
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W.-K. Suh, A. Tafuri, N. N. Berg-Brown, A. Shahinian, S. Plyte, G. S. Duncan, H. Okada, A. Wakeham, B. Odermatt, P. S. Ohashi, et al. The Inducible Costimulator Plays the Major Costimulatory Role in Humoral Immune Responses in the Absence of CD28 J. Immunol., May 15, 2004; 172(10): 5917 - 5923. [Abstract] [Full Text] [PDF]
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T. Ito, R. Amakawa, M. Inaba, T. Hori, M. Ota, K. Nakamura, M. Takebayashi, M. Miyaji, T. Yoshimura, K. Inaba, et al. Plasmacytoid Dendritic Cells Regulate Th Cell Responses through OX40 Ligand and Type I IFNs J. Immunol., April 1, 2004; 172(7): 4253 - 4259. [Abstract] [Full Text] [PDF]
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 M. Kohyama, D. Sugahara, S. Sugiyama, H. Yagita, K. Okumura, and N. Hozumi Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen PNAS, March 23, 2004; 101(12): 4192 - 4197. [Abstract] [Full Text] [PDF]
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Y. Arimura, F. Shiroki, S. Kuwahara, H. Kato, U. Dianzani, T. Uchiyama, and J. Yagi Akt Is a Neutral Amplifier for Th Cell Differentiation J. Biol. Chem., March 19, 2004; 279(12): 11408 - 11416. [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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K. Attanavanich and J. F. Kearney Marginal Zone, but Not Follicular B Cells, Are Potent Activators of Naive CD4 T Cells J. Immunol., January 15, 2004; 172(2): 803 - 811. [Abstract] [Full Text] [PDF]
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A. B. Stavitsky Regulation of Granulomatous Inflammation in Experimental Models of Schistosomiasis Infect. Immun., January 1, 2004; 72(1): 1 - 12. [Full Text] [PDF]
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H. M. Finney, A. N. Akbar, and A. D. G. Lawson Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCR{zeta} Chain J. Immunol., January 1, 2004; 172(1): 104 - 113. [Abstract] [Full Text] [PDF]
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H. Iwai, M. Abe, S. Hirose, F. Tsushima, K. Tezuka, H. Akiba, H. Yagita, K. Okumura, H. Kohsaka, N. Miyasaka, et al. Involvement of Inducible Costimulator-B7 Homologous Protein Costimulatory Pathway in Murine Lupus Nephritis J. Immunol., September 15, 2003; 171(6): 2848 - 2854. [Abstract] [Full Text] [PDF]
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 N. Ardjomand, J. C. McAlister, N. J. Rogers, P. H. Tan, A. J. T. George, and D. F. P. Larkin Modulation of Costimulation by CD28 and CD154 Alters the Kinetics and Cellular Characteristics of Corneal Allograft Rejection Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3899 - 3905. [Abstract] [Full Text] [PDF]
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S.-C. Wong, E. Oh, C.-H. Ng, and K.-P. Lam Impaired germinal center formation and recall T-cell-dependent immune responses in mice lacking the costimulatory ligand B7-H2 Blood, August 15, 2003; 102(4): 1381 - 1388. [Abstract] [Full Text] [PDF]
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J. Yagi, Y. Arimura, U. Dianzani, T. Uede, T. Okamoto, and T. Uchiyama Regulatory Roles of IL-2 and IL-4 in H4/Inducible Costimulator Expression on Activated CD4+ T Cells During Th Cell Development J. Immunol., July 15, 2003; 171(2): 783 - 794. [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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 H. Futamatsu, J.-i. Suzuki, H. Kosuge, O. Yokoseki, M. Kamada, H. Ito, M. Inobe, M. Isobe, and T. Uede Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway Cardiovasc Res, July 1, 2003; 59(1): 95 - 104. [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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J. E. Buhlmann, S. K. Elkin, and A. H. Sharpe A Role for the B7-1/B7-2:CD28/CTLA-4 Pathway During Negative Selection J. Immunol., June 1, 2003; 170(11): 5421 - 5428. [Abstract] [Full Text] [PDF]
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S. Kurosawa, A. C. Myers, L. Chen, S. Wang, J. Ni, J. R. Plitt, N. M. Heller, B. S. Bochner, and R. P. Schleimer Expression of the Costimulatory Molecule B7-H2 (Inducible Costimulator Ligand) by Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2003; 28(5): 563 - 573. [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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Y. Harada, D. Ohgai, R. Watanabe, K. Okano, O. Koiwai, K. Tanabe, H. Toma, A. Altman, and R. Abe A Single Amino Acid Alteration in Cytoplasmic Domain Determines IL-2 Promoter Activation by Ligation of CD28 but Not Inducible Costimulator (ICOS) J. Exp. Med., January 20, 2003; 197(2): 257 - 262. [Abstract] [Full Text] [PDF]
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L. S. K. Walker, H. E. Wiggett, F. M. C. Gaspal, C. R. Raykundalia, M. D. Goodall, K.-M. Toellner, and P. J. L. Lane Established T Cell-Driven Germinal Center B Cell Proliferation Is Independent of CD28 Signaling but Is Tightly Regulated Through CTLA-4 J. Immunol., January 1, 2003; 170(1): 91 - 98. [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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H. Iwai, Y. Kozono, S. Hirose, H. Akiba, H. Yagita, K. Okumura, H. Kohsaka, N. Miyasaka, and M. Azuma Amelioration of Collagen-Induced Arthritis by Blockade of Inducible Costimulator-B7 Homologous Protein Costimulation J. Immunol., October 15, 2002; 169(8): 4332 - 4339. [Abstract] [Full Text] [PDF]
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K. Ogasawara, S. K. Yoshinaga, and L. L. Lanier Inducible Costimulator Costimulates Cytotoxic Activity and IFN-{gamma} Production in Activated Murine NK Cells J. Immunol., October 1, 2002; 169(7): 3676 - 3685. [Abstract] [Full Text] [PDF]
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E. N. Villegas, L. A. Lieberman, N. Mason, S. L. Blass, V. P. Zediak, R. Peach, T. Horan, S. Yoshinaga, and C. A. Hunter A Role for Inducible Costimulator Protein in the CD28- Independent Mechanism of Resistance to Toxoplasma gondii J. Immunol., July 15, 2002; 169(2): 937 - 943. [Abstract] [Full Text] [PDF]
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L. Liang, E. M. Porter, and W. C. Sha Constitutive Expression of the B7h Ligand for Inducible Costimulator on Naive B Cells Is Extinguished after Activation by Distinct B Cell Receptor and Interleukin 4 Receptor-mediated Pathways and Can Be Rescued by CD40 Signaling J. Exp. Med., July 1, 2002; 196(1): 97 - 108. [Abstract] [Full Text] [PDF]
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Y. Arimura, H. Kato, U. Dianzani, T. Okamoto, S. Kamekura, D. Buonfiglio, T. Miyoshi-Akiyama, T. Uchiyama, and J. Yagi A co-stimulatory molecule on activated T cells, H4/ICOS, delivers specific signals in Th cells and regulates their responses Int. Immunol., June 1, 2002; 14(6): 555 - 566. [Abstract] [Full Text] [PDF]
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P. Wahl, R. Schoop, G. Bilic, J. Neuweiler, M. Le Hir, S. K. Yoshinaga, and R. P. Wuthrich Renal Tubular Epithelial Expression of the Costimulatory Molecule B7RP-1 (Inducible Costimulator Ligand) J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1517 - 1526. [Abstract] [Full Text] [PDF]
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J. Deng, R. H. Dekruyff, G. J. Freeman, D. T. Umetsu, and S. Levy Critical role of CD81 in cognate T-B cell interactions leading to Th2 responses Int. Immunol., May 1, 2002; 14(5): 513 - 523. [Abstract] [Full Text] [PDF]
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A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [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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G. Richter, M. Hayden-Ledbetter, M. Irgang, J. A. Ledbetter, J. Westermann, I. Korner, K. Daemen, E. A. Clark, A. Aicher, and A. Pezzutto Tumor Necrosis Factor-alpha Regulates the Expression of Inducible Costimulator Receptor Ligand on CD34+ Progenitor Cells during Differentiation into Antigen Presenting Cells J. Biol. Chem., November 30, 2001; 276(49): 45686 - 45693. [Abstract] [Full Text] [PDF]
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S.-h. Ogawa, G. Nagamatsu, M. Watanabe, S. Watanabe, T. Hayashi, S. Horita, K. Nitta, H. Nihei, K. Tezuka, and R. Abe Opposing Effects of Anti-Activation-Inducible Lymphocyte- Immunomodulatory Molecule/Inducible Costimulator Antibody on the Development of Acute Versus Chronic Graft-Versus-Host Disease J. Immunol., November 15, 2001; 167(10): 5741 - 5748. [Abstract] [Full Text] [PDF]
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J. Hernandez, S. Aung, W. L. Redmond, and L. A. Sherman Phenotypic and Functional Analysis of Cd8+ T Cells Undergoing Peripheral Deletion in Response to Cross-Presentation of Self-Antigen J. Exp. Med., September 17, 2001; 194(6): 707 - 718. [Abstract] [Full Text] [PDF]
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A. G. Tesciuba, S. Subudhi, R. P. Rother, S. J. Faas, A. M. Frantz, D. Elliot, J. Weinstock, L. A. Matis, J. A. Bluestone, and A. I. Sperling Inducible Costimulator Regulates Th2-Mediated Inflammation, but Not Th2 Differentiation, in a Model of Allergic Airway Disease J. Immunol., August 15, 2001; 167(4): 1996 - 2003. [Abstract] [Full Text] [PDF]
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J. J. Wallin, L. Liang, A. Bakardjiev, and W. C. Sha Enhancement of CD8+ T Cell Responses by ICOS/B7h Costimulation J. Immunol., July 1, 2001; 167(1): 132 - 139. [Abstract] [Full Text] [PDF]
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J. Guo, M. Stolina, J. V. Bready, S. Yin, T. Horan, S. K. Yoshinaga, and G. Senaldi Stimulatory Effects of B7-Related Protein-1 on Cellular and Humoral Immune Responses in Mice J. Immunol., May 1, 2001; 166(9): 5578 - 5584. [Abstract] [Full Text] [PDF]
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S. Wang, G. Zhu, K. Tamada, L. Chen, and J. Bajorath Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function J. Exp. Med., April 15, 2002; 195(8): 1033 - 1041. [Abstract] [Full Text] [PDF]
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