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*
Abramson Family Cancer Research Institute and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA 19104;
National Institute of Diabetes and Digestive and Kidney Diseases, Navy Transplantation and Autoimmunity Branch, Naval Medical Research Center, Bethesda, MD 20889;
Research Institute for Biological Sciences, Science University of Tokyo, Chiba, Japan; and
Pharmaceutical Frontier Research Laboratories, JT Incorporated, Kangawa, Japan
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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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ICOS (AILIM) is the third member of the CD28 family whose role in the immune response remains to be elucidated (15, 16). Although ICOS possesses costimulatory activity, it differs from CD28 in at least three important ways: 1) ICOS costimulation results in the increased production of IL-4, IL-5, and IL-10 but not IL-2 (15). 2) The ICOS ligand, B7RP-1 (B7h, GL50, and B7H2) is structurally related to the B7 molecules but binds neither CD28 nor CTLA-4 (17, 18, 19, 20). Likewise, ICOS does not bind either CD80 or CD86. Thus, there is no competition for ligand binding between CTLA-4 and ICOS. 3) ICOS, like CTLA-4, is induced on the T cell surface upon cell activation (15, 21).
ICOS, unlike CTLA-4, does not bind CD80 or CD86 and generates a qualitatively different signal than CD28. Given CTLA-4’s proposed role as the gatekeeper to T cell activation (11), we investigated whether CTLA-4 ligation could prevent ICOS-mediated costimulation. CTLA-4 cross-linking can effectively block ICOS costimulation. The addition of exogenous IL-2 not only overcomes this block, but also greatly augments the effects of ICOS costimulation. To further explore the relationship between ICOS costimulation and IL-2, we show that IL-2 is necessary for costimulation of CD4 T cells. However, ICOS costimulation is not sufficient to sustain growth, and ICOS-costimulated T cells undergo apoptosis in the absence of exogenous IL-2.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBLs were isolated by Percoll (Pharmacia Biotech, Uppsala, Sweden) gradient centrifugation from leukopacks obtained following apheresis of healthy donors. CD4+ T cells were purified by negative selection using magnetic beads (Dynal, Lake Success, NY) as described previously (3) and were routinely >98% CD3+, >98% CD28+, and <3% CD8+ as judged by flow cytometry.
Abs, bead preparation, and cell stimulation
The mouse anti-human AILIM/ICOS mAb, clone JMAb-52, was generated by immunizing female BALB/c mice with the membrane fraction of human AILIM/ICOS-expressing Chinese hamster ovary cells. Anti-CD3 (OKT3) (22), anti-CTLA-4 (ER5.3D6) (23), anti-CD28 (9.3) (24), anti-glycophorin A (GLY)3 (clone HB-8162; American Type Culture Collection, Manassas, VA), and anti-AILIM/ICOS (JMAb52) covalently attached to polyurethane-coated tosyl-activated Dynalbeads (Dynal) per the manufacturer’s instructions. Beads were prepared with a constant, suboptimal amount of OKT3 (12.5% of total protein coated on the beads), and various ratios (indicated in the text) of anti-ICOS, -CTLA-4, -CD28, and GLY. Polyclonal goat anti-human IL-2 Abs were obtained from R&D Systems (Minneapolis, MN).
Beads were mixed with CD4 T cells at a 3:1 ratio. Where indicated, 300 U/ml of IL-2 (Chiron Therapeutics, Emeryville CA) were added to the cultures. Alternatively, cells were stimulated with 5 µg/ml PHA (Sigma, St. Louis, MO) and 300 U/ml IL-2. Cells were cultured at 1 x 106/ml as previously described (14). Cell proliferation assays were conducted in 96-well plates using 1 x 105 cells. Cultures were pulsed with 1 µCi of [3H]thymidine for 18 h before harvest.
Quantitative RT-PCR
RNA was purified and reverse transcribed as described previously
(14). Primers and probes to detect IL-2, IL-4, IL-10,
IL-13, and 28S rRNA were designed using Primer Express software
(Applied Biosytems, Foster City, CA), and their sequences are available
upon request. Real-time PCR amplification and product detection was
performed using the ABI Prism 7700 (Applied Biosystems) as recommended
by the manufacturer. Results were normalized to 28S rRNA levels and
relative expression was determined by using the 
Ct method
according to the manufacturer’s protocol.
Cell surface staining
A total of 5 x 105 CD4 T cells were incubated with anti-AILIM (ICOS) or an equivalent amount of an isotype control (BD PharMingen, San Diego, CA) for 30 min at 4°C. After being washed, the cells were incubated with a PE-conjugated goat anti-mouse Ab. Samples were analyzed on a FACSCalibur (BD Biosciences, Mountain View, CA) after gating on live lymphocytes based on a standard light scatter histogram (integral forward scatter vs log 90°). Apoptosis assays were conducted by washing 1 x 106 cells once in PBS and incubating with annexin V and propidium iodide per the manufacturer’s protocol (R&D Systems). Data were analyzed using WinMIDI software (J. Trotter, Scripps Research Institute, La Jolla, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study ICOS, CTLA-4, and CD28 functional effects, we constructed artificial APCs decorated with Abs to the costimulatory receptors. We used Abs rather than natural ligands because B7-1 and B7-2 bind to both CD28 and CTLA-4. Therefore, the effect of CTLA-4 ligation on ICOS-mediated costimulatory signals was evaluated by stimulating CD4 T cells with magnetic beads containing a fixed, suboptimal level of anti-CD3 coupled with varying amounts of anti-ICOS and anti-CTLA-4. Previous data from other laboratories and ours have indicated that a suboptimal level of CD3 signaling is needed to see the antiproliferative effects of CTLA-4 engagement (13, 25, 26). To simplify nomenclature, immunobeads that contain anti-CD3 coupled with equal amounts of anti-ICOS and anti-CTLA-4 are called 5:5 ICOS/CTLA-4 beads. Likewise, beads that contained three parts anti-ICOS and seven parts anti-CTLA-4 are referred to as 3:7 ICOS/CTLA-4 beads. Corresponding control sets of immunobeads were made using GLY. Glycophorin, a nonbinding control, was chosen over a binding control because only minimal ICOS expression is observed on resting cells.
Only minimal proliferation was seen by CD4 T cells stimulated with
beads containing anti-CD3 and GLY (Fig. 1
). The addition of anti-ICOS to the
beads (5:5 ICOS/GLY) greatly augmented the mitogenic response. The
substitution of anti-CTLA-4 for GLY at an equal ratio to ICOS (5:5
ICOS/CTLA-4 beads) slightly inhibited proliferative responses. However,
dramatic differences in proliferation were observed when cells were
stimulated with beads containing higher ratios of anti-CTLA-4 to
anti-ICOS (3:7 ICOS/GLY and 3:7 ICOS/CTLA-4). Similar findings were
obtained using 1:9 ICOS/CTLA-4 beads, although the overall level of
ICOS-mediated proliferation was reduced. These results indicate that,
when present at sufficiently high concentrations, CTLA-4 engagement
blocked ICOS-mediated proliferation.
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To test the effect of CTLA-4 engagement on ICOS-mediated cytokine
production, we developed a quantitative RT-PCR assay to measure levels
of mRNA encoding IL-4, IL-10, and IL-13. Although IL-13 was not
initially described as a cytokine induced by ICOS costimulation
(15), in preliminary data we found it to be highly
up-regulated by ICOS costimulation. Because stimulation of CD4 T cells
with 3:7 ICOS/GLY and 3:7 ICOS/CTLA-4 beads resulted in vastly
different levels of proliferation, we focused our cytokine transcript
analysis on cells stimulated with these beads. In cells costimulated
with 3:7 ICOS/GLY beads, we noted a 10- to 20-fold increase of the
transcripts encoding IL-4, IL-10, and IL-13 (Fig. 2). An increase in cytokine RNA levels
was not seen in cells stimulated with 3:7 ICOS/CTLA-4 beads. Similar
data were obtained by analyzing the levels of IL-10 in the supernatant
by ELISA (data not shown). These observations indicate that, in
addition to inhibiting ICOS-mediated proliferation, CTLA-4 ligation can
block ICOS-directed cytokine production.
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and data not shown). Addition of IL-2 to
cells stimulated with 3:7 ICOS/GLY beads also resulted in increases of
cytokine transcripts, suggesting synergy between ICOS- and
IL-2-mediated signal transduction (Fig. 2). Thus, ICOS and IL-2 signals
may act cooperatively to activate T cells in a manner that cannot be
inhibited by CTLA-4 engagement. CTLA-4 engagement prevents the up-regulation of ICOS
Because ICOS is induced after T cell activation (15),
we postulated that engagement of CTLA-4 early in the cell activation
process could block the actions of ICOS by preventing its cell surface
up-regulation. To test this hypothesis, we stimulated resting CD4 T
cells with either 3:7 ICOS/GLY or 3:7 ICOS/CTLA-4 beads for 24 h
and assayed for ICOS surface expression. Consistent with this
hypothesis, ICOS up-regulation was not observed in cells stimulated by
the 3:7 ICOS/CTLA-4 beads (Fig. 3).
Because addition of IL-2 to cultures stimulated with 3:7 ICOS/CTLA-4
beads not only restored but greatly augmented cytokine expression (Fig. 2), we reasoned that IL-2 addition would restore ICOS induction in the
3:7 ICOS/CTLA-4 stimulated CD4 T cells. However, we observed only a
partial recovery of ICOS expression following IL-2 addition. This is
surprising given the enhanced production of IL-4, IL-10, and IL-13
observed upon addition of IL-2 to cultures stimulated with 3:7
ICOS/CTLA-4 beads (Fig. 2). Additionally, while ICOS was initially
reported to be absent from human resting cells (15), we
detected low levels of ICOS expression on the surface of resting cells,
confirming our recent studies in rat T cells (Fig. 3)
(21). Despite this low level of expression, we found no
evidence of ICOS up-regulating its own expression as both 3:7 ICOS/GLY
and beads just coated with anti-CD3 and GLY up-regulated ICOS
expression on CD4 T cells equally (Fig. 3A and data not
shown).
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B,
CD28 costimulation induces high levels of ICOS expression on all CD4 T
cells (Fig. 3B). To test the effects of CTLA-4 ligation on
CD28-mediated up-regulation of ICOS, resting CD4 cells were stimulated
with 1:9 CD28/CTLA-4 beads and a matching 1:9 CD28/MHC I control.
Because CD28 is highly expressed on resting cells, we used a binding
control Ab (MHC class I). In cells stimulated with 1:9 CD28/CTLA-4
beads, no up-regulation of ICOS was observed, whereas high levels of
ICOS were seen in cells stimulated with 1:9 CD28/MHC I beads (Fig. 3B). These results indicate that CTLA-4 costimulation can
block ICOS induction mediated by either CD3 or CD28 signals. To confirm
these results and to gain insight into the regulation of ICOS
expression, we examined ICOS mRNA levels by quantitative PCR and found
a very close correlation between RNA level and surface expression (data
not shown), suggesting that ICOS expression is primarily regulated at
the RNA level. CTLA-4 can block ICOS-mediated events on preactivated cells
Because CTLA-4 engagement prevents ICOS up-regulation on resting
cells, we could not determine whether CTLA-4 blocks ICOS signal
transduction. Therefore, we stimulated CD4 T cells with PHA and IL-2,
which resulted in large increase in ICOS surface expression (Fig. 4, inset). Cells were then
washed several times to remove IL-2, restimulated with either 3:7
ICOS/GLY or 3:7 ICOS/CTLA-4 beads, and then harvested 6 h later.
An increase in the transcripts encoding IL-4 and IL-10 was evident in
cells stimulated with 3:7 ICOS/GLY beads but not in cells stimulated
with 3:7 ICOS/CTLA-4. CTLA-4 ligation diminished, but did not
completely prevent, induction of IL-13 by ICOS. Thus, even when high
levels of ICOS are present on the cell surface, CTLA-4 engagement can
block ICOS-mediated costimulation by interfering with ICOS’s signal
transduction pathway.
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The dramatic ability of IL-2 to augment the production of
cytokines from ICOS-costimulated CD4 T cells prompted us to further
explore the relationship between IL-2 and ICOS costimulation. Although
one group reported high levels of IL-2 production upon ICOS
costimulation (20), most groups have reported undetectable
levels of IL-2 in the supernatant (15, 19, 27). We also
failed to detect IL-2 in the supernatant of ICOS-stimulated T cells
(data not shown). However, because IL-2 is an important factor for CD4
T cell growth, we speculated that ICOS costimulation was producing
small levels of IL-2 that were being consumed immediately by the
ICOS-costimulated T cells and thereby not detectable by ELISA. To test
this hypothesis, we isolated RNA from these cells and measured IL-2
transcripts using a quantitative real-time RT-PCR assay. The results
show that 3:7 ICOS/GLY-costimulated T cells produce 30-fold more IL-2
mRNA than CD3 stimulation alone (Fig. 5),
suggesting that small amounts (relative to CD28) of IL-2 are made by
ICOS-costimulated T cells. Interestingly, CTLA-4 engagement prevented
the induction of IL-2 gene expression.
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). A
dose-dependent drop in cellular proliferation was observed in cultures
treated with IL-2 Ab, whereas no effect was seen when a control Ab was
added. Similar results were recently obtained by Yoshinaga and
colleagues using a B7RP-1 fusion protein to stimulate T cells
(27). These results indicate that ICOS-costimulated T
cells produce small amounts of IL-2 that are immediately consumed by
the T cells. Thus, IL-2 is required for induction of proliferation
by ICOS.
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CD4 T cells require IL-2 for sustained growth and proliferation
(28). The minimum quantities of IL-2 produced by
ICOS-costimulated T cells prompted us to investigate whether these
cells were capable of sustained proliferation. T cells costimulated by
either anti-ICOS or anti-CD28 accumulated at equivalent rates
for the first 6 days after stimulation. However, after that point, the
ICOS-costimulated culture stopped growing, whereas the
CD28-costimulated culture continued to expand in agreement with our
previous results (6) (Fig. 7). We saw no synergy between CD28 and
ICOS costimulation, as cells costimulated with ICOS and CD28 (5:5
ICOS/CD28) grew as well as those costimulated with CD28 (data not
shown).
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). The addition of
IL-2 to the ICOS-costimulated cultures prevented the increase in
apoptosis and permitted long-term growth term expansion equivalent to
that seen with CD28 costimulation (Table I and Fig. 7). Thus, ICOS
costimulation is able to provide the necessary proliferative signals to
start cell division, but does not deliver the survival signals needed
to maintain long-term growth.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CTLA-4 is a global attenuator of T cell activation
The role of CTLA-4 as an immune attenuator is clear, yet the mechanism through which it acts remains to be elucidated. Because CTLA-4 inhibits IL-2 production and cell growth, it was initially postulated that CTLA-4 blocks the actions of CD28 (29). Subsequent work using CD28-/- mice showed that CTLA-4 engagement still blocked T cell responses against a cardiac allograft, suggesting that CTLA-4 engagement could inhibit additional costimulatory pathways (30). Given the potency with which ICOS activates T cells in CD28-/- mice (31), it is likely that ICOS costimulation is sufficient to mediate allograft rejection. Thus, our in vitro results demonstrating that CTLA-4 blocks ICOS costimulation are compatible with the in vivo data showing that CTLA-4 ligation blocks cardiac allograft rejection in CD28-/- mice. The observation that CTLA-4 engagement can prevent the up-regulation of ICOS may be relevant to other inducible costimulatory molecules such as OX40 (32), 4-1BB, (33), and CD40 ligand (34). It is possible that CTLA-4 engagement prevents the up-regulation of these costimulatory molecules, representing a global mechanism in which CTLA-4 ligation prevents T cells from becoming activated.
The interplay of costimulatory molecules determines whether an APC–T cell interaction results in T cell activation. CTLA-4’s blockage of CD28 and ICOS signals requires a high CTLA-4:CD28 or ICOS ratio and can be overcome by lowering this ratio (12, 13, 25, 26). This suggests that the role of CTLA-4 could be to serve as a global attenuator of the immune response by raising the threshold of T cell activation (11). This would prevent weak APC–T cell interactions from activating the immune system, thus, minimizing the potential for autoimmune disease.
What is the role of ICOS in the immune system?
Based on the cytokine profile of cells stimulated by ICOS as well
as in vivo data showing high ICOS expression in B cell areas of lymph
nodes, it was suggested that ICOS costimulation promotes a Th2
phenotype (15). Other reports show that the ICOS is
crucial for all CD4 T cell responses in CD28-deficient mice, suggesting
that ICOS serves a redundant role to CD28 (30). Our data,
coupled with the B7RP-1 expression data, suggest that ICOS can initiate
but not sustain an immune response started by a nonprofessional APC.
B7RP-1 is constitutively expressed on B cells and can be induced on
other nonlymphoid cells by TNF-
(18, 35). Immature
dendritic cells, in contrast, express low levels of B7RP-1 and, upon
maturation with LPS, B7RP-1 is no longer detectable, suggesting that
nonprofessional APCs at a site of inflammation may be the highest
expressers of B7RP-1 (20). By adapting the model of
Thompson and Allison, (7), we would argue that CTLA-4
would outcompete CD28 for binding to this low level of B7-1 induced on
nonprofessional APCs and it would not be sufficient to activate T
cells. Likewise, if only low levels of B7RP-1 are induced, CTLA-4
engagement would still prevent ICOS-mediated T cell activation and a
possible aberrant immune response. However, if high levels of B7RP-1
are induced on the cell surface, costimulation through ICOS would
override this CTLA-4 blockage and induce T cell proliferation and
secretion of effector cytokines. Moreover, as we have pointed out here,
ICOS costimulation would not be able to sustain the T cell response by
itself and would either need CD28 costimulation through a professional
APC or exogenous IL-2. Thus, ICOS costimulation could initiate the
immune response but could not sustain this response without IL-2
created from a professional APC–T cell interaction.
The studies presented here reinforce the complex nature of the T cell response. The immune system has established numerous checks and balances to the T cell response to ensure both a prompt and focused response to a pathogen while preventing autoimmune disease. Our results suggest that ICOS’s main role is not to promote a Th2 response, but rather to initiate T cell responses from nonprofessional APCs in the periphery.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. James L. Riley, Department of Molecular and Cellular Engineering, University of Pennsylvania, 421 Curie Boulevard, Biomedical Research Building II/III Room 508, Philadelphia, PA 19104-6160.
3 Abbreviation used in this paper: GLY, anti-glycophorin A Ab.
Received for publication November 30, 2000. Accepted for publication February 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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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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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