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,¶
*
Department of Immunology, National Children’s Medical Research Center, Tokyo, Japan; Divisions of
Rheumatology and
Pathobiology, Department of Internal Medicine, and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; Departments of
¶ Molecular Immunology and
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Oral Surgery, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; and
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Department of Molecular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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expression by
CD8+ T cells in both GVHD models and CD8+ T
cell-mediated cytotoxicity against host-alloantigen in acute GVHD.
However, a clear inhibition of donor CD4+ T cell expansion
and activation has not been observed. On the contrary, in chronic GVHD,
the number of CD4+ T cells producing IL-4 was enhanced by
anti-CD137L mAb treatment. This suggests that the reduction of
CD8+ T cells producing IFN- promotes Th2 cell
differentiation and may result in exacerbation of chronic GVHD. Our
results highlight the effective inactivation of CD8+ T
cells and the lesser effect on CD4+ T cell inactivation by
CD137 blockade. Intervention of the CD137 costimulatory pathway may be
beneficial for some selected diseases in which CD8+ T cells
are major effector or pathogenic cells. Otherwise, a combinatorial
approach will be required for intervention of CD4+ T cell
function. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production, and survival by CD8+ T cells
in vitro (6, 7). The administration of anti-CD137 mAb
or the transduction of CD137L into tumor cells efficiently amplifies
antitumor CTL responses (8, 9, 10). In transplantation models
the in vivo administration of mAb against CD137 enhances acute
graft-vs-host disease (GVHD) by preferential amplification of
CD8+ T cells and accelerates the rejection of
cardiac allograft and skin transplants (6). The studies
using CD137L-deficient mice also revealed the importance of CD137
costimulation in antiviral CTL responses (11, 12, 13). Thus,
the accumulating reports suggest a crucial role of CD137 costimulation
for CD8+ T cell responses. On the other hand, the
influence of CD137 costimulation on CD4+ T cell
responses has been shown, but in some limited situations and to a
lesser extent (6, 14, 15). Although a regulatory effect of
CD137 signal on CD28-mediated Th2 cell development (16)
and a preferential high expression and functional contribution of CD137
by Th2 cells (17) have been reported, little is known
about the actual contribution of CD137 to Th1- and Th2-meditaed immune
responses in vivo. A GVHD can be caused in inbred F1 mice by the injection of T cells of parental origin. The injection of C57BL/6 (B6) splenocytes into F1 mice (referred to as B6 GVH) results in an immunosuppressive acute GVHD (aGVHD) characterized by an anti-host cell-mediated, Th1 cytokine-driven disease (18, 19, 20). By contrast, the injection of splenocytes from the BALB/c or DBA/2 parent into F1 mice (referred to as BALB/c GVH or DBA GVH) results in an immunostimulatory chronic GVHD (cGVHD) characterized by an autoantibody-mediated, Th2 cytokine-driven disease (21, 22, 23). In development of both types of GVHD, multiple costimulatory molecules are involved. It has been shown that blockade of either CD28 or CD40 signals inhibits both types of GVHD (24, 25, 26, 27, 28). In this study we have investigated the effects of CD137 blockade by using mAb against CD137L in both acute and chronic GVHD models and further examined donor cell expansion and effector function in both CD4+ and CD8+ T cells after the treatment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL/6 (B6, H-2b), DBA/2 (H-2d), (BALB/c x C57BL/6)F1 (CBF1, H-2b/d), and (C57BL/6 x DBA/2)F1 (BDF1, H-2b/d) mice were purchased from Japan SLC (Hamamatsu, Shizuoka, Japan). Female C57BL/6 Ly5.1 (B6Ly5.1) mice were provided by Dr. H. Nakauchi (Tsukuba University, Tsukuba, Japan) and were bleed in our animal facility. Donors for bone marrow (BM) were 6 wk old, those for splenocytes were 6–12 wk old, and recipients were 8–9 wk old at the time of BM transplantation (BMT). For in vitro assay, female 6- to 8-wk-old BALB/c (H-2d) and B6 mice were also obtained from SLC. Mice were maintained in a specific pathogen-free microisolator environment. All mice procedures were reviewed and approved by the animal care and use committee of the National Children’s Medical Research Center and the Tokyo Medical and Dental University (Tokyo, Japan).
Monoclonal Abs and flow cytometry
Hybridomas producing anti-mouse CD80 (RM80, rat IgG2a), CD86
(PO3, rat IgG2b), and CD137L (TKS1, rat IgG2a) mAbs were generated and
purified from ascites as described previously (29, 30, 31).
The pyrogen level was <0.01 ng/ml protein, as determined by a
Limulus amebocyte lysate assay. Fab of anti-CD137L mAb
were prepared using immobilized papain (Pierce, Rockford, IL) and were
purified using immobilized Protein L (Pierce). The purity of Fab was
verified by SDS-PAGE analysis. mAbs against the following Ags were used
for immunofluorescence analysis: CD3 (145-2C11, hamster IgG), CD4
(RM4-5, rat IgG2a), CD8 (53-6.7, rat IgG2a), CD45.1/Ly5.1 (A20, mouse
IgG2a), CD45R/B220 (RA3-6B2, rat IgG2a), H-2Kd
(SF1-1.1, mouse IgG2a), H-2Kb (AF6-88.5, mouse
IgG2a), IFN- (XMG1.2, rat IgG1), and IL-4 (BVD4-1D11, rat IgG2b).
All FITC-, PE-, and PerCP-conjugated mAbs were obtained from PharMingen
(San Diego, CA). Multicolor staining for intracellular cytokine and
cell surface Ags was performed as previously described
(32). Flow cytometry and data analyses were performed
using a FACSort, FACSCalibur, and CellQuest software (Becton Dickinson
Immunocytometry Systems, San Jose, CA). Hybridomas producing mAbs
against I-Ab,d,q (M5/114), CD24 (HSA, J11d),
CD45R/B220 (RA3-6B2), CD4 (RL172.4), and CD8 (3.155) were obtained from
the American Tissue Culture Collection (Manassas, VA) and were used as
culture supernatants.
Induction of acute and chronic GVHD and mAb treatment
For induction of aGVHD by BMT, recipient CBF1 mice were lethally irradiated (10.0 Gy), and BM cells (2.5 x 107) from B6 mice and splenocytes (2.5 x 107) from either B6 or B6/Ly5.1 mice were injected i.v. as described previously (26). A control group of mice received BM cells alone. The recipient mice received BM, and splenocytes (referred as BMS mice) were treated with control rat Ig (Sigma, St. Louis, MO), anti-CD137L mAb, or anti-CD80 and CD86 (CD80/86) mAbs. Two hundred micrograms of each mAb was administered i.p. on days 0, 1, and 2 and every other day until day 21 post-BMT for 12 times.
For induction of cGVHD, unirradiated BDF1 recipients received 1 x 108 splenocytes by i.v. injection. Two hundred micrograms of control rat Ig or anti-CD137L mAb was administrated i.p. three times a week for 4 wk. In some experiments DBA/2 splenocytes were treated with anti-I-A, anti-CD24, and anti-CD8 mAbs and rabbit compliment to deplete APC and CD8+ T cells. As assessed by flow cytometry, this procedure resulted in <1% contaminating CD8+ T cells and >85% purity of CD4+ T cells. BDF1 recipients received 3 x 107 CD8-depleted T cells and were treated with mAb as described above.
Measurement of anti-host cytotoxicity
Individual splenocytes from GVHD mice were treated with anti-CD24, anti-I-A, and anti-CD4 mAbs and rabbit complement. Then, CD8-enriched T cell fractions were obtained and used as effector cells. Cytotoxicity against A20 (H-2d) or EL-4 (H-2b) was measured by a standard 6-h 51Cr release assay.
Measurements of serum IgE and autoantibody
Mice were bled by retro-orbital venipuncture, and serum samples were individually aliquoted and stored at -80°C. Quantitations of total IgE and anti-dsDNA Ab were performed by ELISA as described previously (29, 33).
Measurement of IL-4 production in MLR
Splenocytes from BALB/c mice were treated with anti-CD24,
anti-I-A, anti-CD45R/B220, and either anti-CD4 or
anti-CD8 mAbs and rabbit complement. The purities of
CD4+ and CD8+ T cell
fractions was confirmed to be >95% CD4+ T cells
and >90% CD8+ T cells by flow cytometry. For
MLR, CD4+ T cells (1 x
106/well) were cocultured with mitomycin
C-treated splenocytes (1 x 106/well) from
B6 mice in 24-well plates in the presence or the absence of
anti-CD137L (10 µg/ml) or anti-IFN- (R4-6A2, rat IgG1, 5
µg/ml). To determine the effect of CD8+ T
cells, CD8+ T cells (0.5 x
106/well) were further added to the wells. On day
7, IL-2 (PharMingen; 100 U/ml) was added, and cells were cultured for
an additional 2 days. Cells were harvested, rested in the medium alone
for 8 h, and then restimulated in the anti-CD3 (2C11, 10
µg/ml) mAb-coated plates. After 48 h supernatants were collected
for assessment of IL-4 production. ELISA for IL-4 was performed
according to the protocols recommended by the manufacturer
(eBioscience, San Diego, CA).
Statistical analyses
Significant differences between experimental groups were analyzed by the Mann-Whitney test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that CD137 is induced on T cells in
allogeneic responses (34) and the administration of
agonistic anti-CD137 mAb enhanced allogeneic CTL responses in aGVHD
mice (6). To investigate the direct role of natural ligand
for CD137, we first examined the effect of anti-CD137L mAb
treatment on the development of both acute and chronic GVHD using
parent into F1 models. For aGVHD, BM and
splenocytes from donor B6 mice were transferred into lethally
irradiated CBF1 mice and were treated with anti-CD137L mAb for 3 wk
just after BMT. All mice that received BM and splenocytes from B6 mice
(referred to as BMS mice) showed significant weight loss and died by
day 70, while mice that received BM cell alone (referred to as BM mice)
survived >100 days, with a gradual increase in body weight (Fig. 1
). Consistent with our previous report
(26), treatment with anti-CD80/86 mAbs almost
completely ameliorated the lethality of aGVHD. Treatment with
anti-CD137L mAb failed to prevent early death by aGVHD within 1 mo;
however, the survivors maintained their body weights as well as the
anti-CD80/86-treated mice, and the final survival rate was 43% on
day 100. We failed to observe a clear amelioration of lymphocyte
recovery in peripheral blood and of histology in spleen (data not
shown). These results demonstrated that blockade of CD137L interaction
partially ameliorated the lethality of aGVHD.
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, A and B).
Surprisingly, the anti-CD137L mAb treatment enhanced the production
of IgE and autoantibody, especially at the early time point. The
evaluation of IgG subclasses of anti-dsDNA Ab revealed the
predominant enhancement of IgG1 and IgG2b subclasses by anti-CD137L
mAb treatment (Fig. 2C). Similar results were obtained by
treatment with Fab of anti-CD137L mAb (Fig. 2D),
suggesting that the elevated IgE production may not be due to direct
activation of B cells by cross-linking of CD137L. These results suggest
that blockade of the CD137 pathway by mAb treatment accelerated the
development of cGVHD.
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In both GVHD models maximum donor T cell expansion was observed by
1–2 wk (32, 35). Therefore, we examined the splenic
phenotype at 2 wk after transfer. As shown in Fig. 3A, the total cell number in
the spleen was clearly reduced in the control Ig-treated aGVHD mice,
and anti-CD137L mAb treatment improved the reduction of splenocytes
as well as in the mice treated with anti-CD80/86 mAbs. These
results suggest that anti-CD137L mAb treatment improved the
elimination of host cells by anti-host CTL. In the anti-CD137L
mAb-treated mice, expansion of donor CD8+ T
cells, but not CD4+ T cells, was significantly
inhibited. On the contrary, the mice treated with anti-CD80/86 mAb
did not show a reduction in donor CD8+ T
cells.
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B). The percentage of
donor (H-2b-) cells in the control
Ig-treated mice was 37.6 ± 13.8%, and this was inhibited to
17.1 ± 2.7% by anti-CD137L treatment, suggesting the
expansion of host B cells by anti-CD137L mAb treatment. Treatment
with anti-CD137L mAb reduced donor T cell expansion; this was
especially obvious in the CD8+ T subset. These
results suggest that anti-CD137L mAb treatment preferentially
inhibits expansion of CD8 T cells, and this may result in preserved
host cells and the activation of host B cells. Functional ability by CD8+ T cells is clearly inhibited by anti-CD137L mAb treatment
We next examined cytokine expression on donor T cells. In aGVHD
mice anti-CD80/86 mAb treatment significantly inhibited IFN-
expression by both CD4 and CD8 T cells, while anti-CD137L mAb
treatment had a superior inhibitory effect in the
CD8+ subset (Fig. 4A). In cGVHD mice, although
IFN- expression by CD8+ T cells was
efficiently inhibited as well as in aGVHD mice, both IFN- and IL-4
expression by CD4+ T cells was enhanced by
anti-CD137L treatment (Fig. 4B). To assess the cytolytic
ability of CD8 T cells, we examined cytotoxicity against host
alloantigen using a CD8+-enriched fraction of
recipient splenocytes at 14 days. As well as IFN- expression on
CD8+ T cells, cytotoxicity against host
alloantigen was efficiently inhibited by anti-CD137L treatment in
the aGVHD model, whereas the anti-CD80/86 mAb treatment did not
have a significant effect (Fig. 5A). Consistent with previous
reports (21, 35, 36), an obvious cytotoxicity against host
alloantigen was not observed in the DBA/2-cGVHD mice, and cytotoxicity
was not affected by anti-CD137L treatment (Fig. 5B).
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To determine the contribution of donor CD8+
T cells in enhancement of Ig production by anti-CD137L treatment in
cGVHD mice, we examined the effect of anti-CD137L mAb treatment in
a DBA-GVH model induced by CD8+ T cell-depleted
donor T cells. As shown in Fig. 6, A and B, the enhancement of IgE and autoantibody
production by anti-CD137L treatment became mild without donor
CD8+ T cells. These results suggest a partial
involvement of donor CD8+ T cells in the
acceleration of cGVHD by anti-CD137L treatment.
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on IL-4
production in primary CD4+ T cell MLR. As shown
in Fig. 6C, CD4+ T cells stimulated by
allogeneic splenocytes produced moderate IL-4, and this was minimally
induced by the addition of anti-CD137L mAb during primary
responses. Interestingly, the addition of neutralizing anti-IFN-
mAb dramatically enhanced IL-4 production. When
CD8+ T cells were added to similar MLR cultures,
IL-4 production was clearly reduced. The addition of anti-CD137L
mAb or anti-IFN- mAb partially rescued the reduced IL-4
production at similar levels. These results demonstrated that IFN-
may play a key regulatory role in the generation of IL-4-producing
CD4+ T cells in a primary MLR, and the blockade
of CD137L may preferentially inhibit CD8+ T cell
activation, resulting in reduced production of IFN-. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our lethal aGVHD model, blockade of CD137L ameliorated the
lethality, but it was not as efficient as blockade of CD80/86. Blockade
of CD137 failed to prevent early death within 1 mo post-BMT. However,
the survivors maintained their body weights comparable to the
anti-CD80/86 mAb-treated group, and late death was not observed.
These results suggest that the inhibitory effect of CD137 blockade is
not sufficient in an initial GVH response, but is enough in the late
responses of GVH reactions. The other characteristic result of CD137
blockade is less of an inhibitory effect on CD4+
T cell expansion and activation despite the efficient suppression of
CD8+ T cell activation. CD137 is minimally
expressed on resting T cells and is inducible on both activated
CD4+ and CD8+ T cells.
However, Tan et al. (34) reported a preferentially high
and rapid induction of CD8+ T cells after
allogeneic stimulation and a requirement for multiple cell divisions
for the induction of CD137 in both CD4+ and
CD8+ T cells. Stimulation through CD137 by an
agonistic anti-CD137 mAb dramatically augmented proliferation and
IFN- production by CD8+ T cells, but CD137
signals had a weak effect on proliferation of
CD4+ T cells (34). In contrast a
recent report demonstrated that anti-CD137 mAb increased aGVHD
induced by CD8+ or CD4+ T
cells infused into sublethally irradiated MHC class I- or MHC class
II-only disparate recipients (37). However, in their
results proliferative responses and Th1 and Th2 cytokine production by
CD4+ T cells were not affected by the treatment.
Therefore, we favor the preferential involvement of CD137 in
CD8+ T cell-mediated allogeneic responses. A
prior report demonstrated that both acute and chronic GVHD share a
common event, the recognition of allogeneic MHC class II molecules by
donor CD4+ T cells, which results in increased
IL-2 production and proliferation during the first 2 days after
parental cell transfer (38). However, the induction of
CD137 on CD4+ T cells is not enough at this early
period; therefore, the blockade of CD137 by anti-CD137L mAb may be
invalid at such a critical period for inhibition of initial
CD4+ T cell activation. This may result in
partial amelioration by blockade of CD137 and a lesser effect on
CD4+ T cell inactivation in aGVHD mice.
In cGVHD our results showed that anti-CD137L mAb treatment induced
obvious splenomegaly, early production of autoantibody and IgE, and
increased numbers of IL-4-producing CD4+ T cells,
which are characteristic features of cGVHD. However, despite these
observations donor T cell expansion was consistently inhibited by
anti-CD137L mAb treatment, especially within the CD8 subset. Prior
reports demonstrated the importance of the regulatory role of donor
CD8+ T cells in the development of cGVHD
(35, 36, 39). We have also demonstrated a critical role of
CD8+ T cell expansion in the early response for
regulation of the consequent Th2-mediated humoral immune responses in
BALB/c GVH reactions (32). Our results suggest that
blockade of CD137 preferentially inhibits CD8+ T
cell expansion and activation. This may reduce IFN- production,
which regulates Th2 cell differentiation, and may result in the
augmentation of Th2 cell differentiation and activation. This was
further confirmed by the in vitro MLR experiments. By the addition of
CD8+ T cells, IL-4 production from primary
CD4+ T cell MLR cultures was clearly reduced, and
this was enhanced by CD137L blockade as well as neutralization of
IFN-. In the absence of CD8+ T cells, IL-4
production was not affected by CD137 blockade, but neutralization of
IFN- efficiently enhanced IL-4 production by
CD4+ T cells. This suggests that CD137 blockade
may inhibit IFN- produced by CD8+ T cells, but
not by CD4+ T and other cells. Consistently,
depletion of donor CD8+ T cells diminished the
effect of anti-CD137L mAb treatment in the in vivo model of cGVHD,
In the absence of donor CD8+ T cells, the mice
treated with anti-CD137L mAb still exhibited higher autoantibody
and IgE production. These results suggest the involvement of other
effector cells in this mechanism. NK and NKT cells may be possible
candidates, since the expression and functional involvement of CD137 by
NK and NKT cells have been shown (40, 41). Further studies
will be required to clarify this issue. The prolonged administration
with anti-CD137L mAb for 6 wk did not clearly improve the
manifestation of cGVHD (not shown), suggesting the failure of blockade
of already activated Th2 cells by anti-CD137L mAb treatment.
Similarly, invalid effects have been shown in Th1- and Th2-mediated
experimental leishmaniasis. The administration of anti-CD137L mAb
was of no effect on either Th2 cell-mediated susceptibility in BALB/c
mice or Th1 cell-mediated resistance in B6 mice (31). On
the one hand, Mittler et al. (42) demonstrated that an
initial treatment with an agonistic anti-4-1BB mAb inhibited T
cell-dependent humoral immune responses independent of
CD8+ T cells, whereas the same treatment enhanced
CD8+ T cell-mediated aGVHD (6).
Although we cannot simply reverse the results between the agonistic
anti-CD137 mAb and the blocking anti-CD137L mAb, such a
CD137-mediated inhibition in humoral immunity may overlap with the
effect of CD137 blockade in CD8+ T cells.
In this study we clearly demonstrated the effective inactivation of CD8+ T cells in both acute and chronic GVHD and a lesser effect on inactivation of CD4+ T cells by blockade of CD137 costimulation. Our present results have confirmed the preferential function of CD137-mediated costimulation in CD8+ T cell in acute and chronic GVHD models using an antagonistic anti-CD137L mAb. Among the multiple costimulatory molecules, CD137 may be a unique and powerful costimulator for CD8+ T cells, but not for CD4+ T cells. Intervention in the CD137 costimulatory pathway may be effective for some selected diseases in which CD8+ T cells have the major effect or pathogenic cells. Otherwise, a combined approach will be required for intervention in residual functional CD4+ T cells.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Miyuki Azuma, Department of Molecular Immunology, Division of Oral Health Sciences, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan. E-mail address: miyuki.mim{at}tmd.ac.jp
3 Abbreviations used in this paper: CD137L, CD137 ligand; BM, bone marrow; BMS, bone marrow and splenocytes; BMT, bone marrow transplantation; GVHD, graft-vs-host disease; aGVHD, acute GVHD; cGVHD, chronic GVHD.
Received for publication March 30, 2001. Accepted for publication August 31, 2001.
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). The mice
received BM cells and splenocytes (BMS mice) that were treated with
control rat Ig (•), anti-CD137L (
), or anti-CD80/86 mAbs
(
) 12 times. Each group consists of 12–14 mice. Survival rates
(A) and mean body weights (B) are shown.
Data are representative of two independent experiments with similar
results.
), control BMS
(
), anti-CD137L-treated BMS (
), and anti-CD80/86-treated
BMS (
) mice are shown. The percentages of H-2d- donor
cells were 83.8 ± 1.0, 92.1 ± 1.5, and 90.6 ± 0.6%
in control, anti-CD137L-treated, and anti-CD80/86 mAb-treated
BMS mice, respectively. B, The numbers of total
splenocytes in age-matched intact BDF1 (
