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* Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; and
Department of Immunology, Tokai University, Isehara, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in the
presence of APCs and OVA peptide. In addition, DCs from
CD100-/- mice display poor allostimulatory capabilities
and defects in costimulatory molecule expression and IL-12 production.
The addition of exogenous soluble rCD100 restores normal functions in
CD100-/- DCs and further enhances functions of normal
DCs. Furthermore, treatment of Ag-pulsed DCs with both soluble CD100
and anti-CD40 before immunization significantly enhances their
immunogenicity. This treatment elicits improved T cell priming in vivo,
enhancing both primary and memory T cell responses. Collectively, these
results demonstrate that CD100, which enhances the maturation of DCs,
is essential in the activation and differentiation of Ag-specific T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD100 uses CD72 as a receptor in lymphoid tissues (15), although plexin-B1 may function as a receptor in nonlymphoid tissues (19). CD100-deficient (CD100-/-) mice have multiple defects in lymphoid tissues, but not in other tissues in which CD100 and plexin-B1 are abundantly expressed, suggesting that the interaction between CD100 and CD72 plays a nonredundant role in the immune system (16). CD72 functions as a negative regulator of B cell responses by recruiting a tyrosine phosphatase, SHP-1, to immunoreceptor tyrosine-based inhibitory motifs (20, 21). CD100 binding induces the dephosphorylation of the CD72 tyrosines. SHP-1 then dissociates from CD72, leading to the enhancement of B cell activation (14, 15, 16). As expected, both in vitro B cell responses and in vivo Ab responses are impaired in CD100-/- mice (16). It is noteworthy that CD100-/- mice also display severe impairments in the Ag priming of T cells, although CD100-/- T cells respond normally to either mitogens or anti-CD3 stimulation (16). In contrast, the Ag priming of T cells has been demonstrated to become enhanced in CD100 transgenic (Tg) mice in which serum levels of sCD100 are significantly elevated (18). This result suggests that CD100 is important in the interaction of T cells with APCs, as CD72 is also expressed by APCs, such as macrophages and DCs (22). However, it still remains to be determined how CD100 plays a role in T cell activation and whether CD100 is involved in pathogenic immune responses.
In this study, we show that CD100 is critical for the induction of experimental autoimmune encephalomyelitis (EAE) and for the activation and differentiation of T cells stimulated by Ag-primed APCs. Furthermore, our findings demonstrate the involvement of CD100 in the maturation of DCs, which is necessary for the stimulation of Ag-specific T cell responses.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To generate CD100-/- mice on either the
C57BL/6 or BALB/c backgrounds, CD100-/- mice
were backcrossed for more than eight generations with C57BL/6 or BALB/c
mice. Mice expressing the Tg OVA (OVA323–339)-specific 
TCR
(OVA-TCR Tg) on a BALB/c background have been previously described
(23, 24). OVA-TCR Tg mice on a
CD100-/- background were established by
crossing the OVA-TCR Tg mice with CD100-/-
BALB/c mice. Mice were maintained in a pathogen-free environment.
Induction of EAE
EAE was induced in 8- to 12-wk-old
CD100+/+ or CD100-/- mice
on a C57BL/6 background following s.c. injection of 100 µg mouse/rat
myelin oligodendrocyte glycoprotein (MOG) peptide
(MEVGWYRSPFSRVVHLYRNGK) and pertussis toxin (100 ng; List Biological
Labs, Campbell, CA), as described previously (25). For T
cell priming analysis for MOG or OVA, 8- to 12-wk-old
CD100+/+ or CD100-/- mice
on a C57BL/6 background were immunized with 100 µg MOG or OVA in CFA
into the hind footpads. Seven days after the immunization,
CD4+ T cells were purified from the draining
lymph nodes by MACS (Miltenyi Biotec, Bergisch Gladbach,
Germany), and 1 x 105 cells were stimulated
for 72 h with MOG or OVA in the presence of irradiated (3000 rad)
splenocytes (1 x 106 cells) from C57BL/6
mice. For proliferation assay, cells were pulsed with 2 µCi
[3H]thymidine for the last 12 h. Levels of
IL-4 and IFN- in the culture supernatants were measured using ELISA
kit (R&D Systems, Minneapolis, MN).
Stimulation of naive TCR-Tg T cells
CD62LbrightCD4+
naive T cells from OVA-TCR Tg mice were purified by positive selection
using a FACSVantage flow cytometer (BD Biosciences, Mountain View,
CA). The purity of the cells was >99%. In the proliferation
assays, 2 x 104 isolated naive T cells were
stimulated for 72 h with varying concentrations of OVA peptide in
the presence of irradiated (3000 rad) splenocytes (2 x
105 cells) derived from either
CD100+/+ or CD100-/- mice
on a BALB/c background in 96-well microtiter plates. Cells were pulsed
with 2 µCi [3H]thymidine for the last 12
h. In the cytokine assays, 1 x 105 naive T
cells were cultured for 1 wk with varying concentrations of OVA peptide
in the presence of 2 x 106 irradiated
splenocytes derived from CD100+/+ or
CD100-/- mice in 24-well plates.
CD4+ T cells were prepared using MACS, and 1
x 105 cells were restimulated for 48 h with
5 µg/ml anti-CD3 (2C11; BD PharMingen, San Diego, CA) coated on
the plates in the presence of 5 µg/ml anti-CD28 mAb (37.51; BD
PharMingen) in round-bottom 96-well plates, as previously described
(24). The levels of IL-4 and IFN- were measured by
ELISA.
DC-induced MLR
DCs were generated from the bone marrow progenitors of CD100+/+ or CD100-/- C57BL/6 mice (6–12 wk old) using GM-CSF, as previously described (26, 27). In most of experiments, we used bone marrow-derived DCs 6 days after in vitro culture with GM-CSF because the expression of costimulatory molecules and allostimulatory capacities of DCs at this stage is significantly low compared with splenic and in vitro maturated DCs. CD4+ T cells (5 x 104 cells/well) derived from CD100+/+ or CD100-/- BALB/c mice were cultured with irradiated (3000 rad) DCs derived from CD100+/+ or CD100-/- C57BL/6 mice for 72 h and pulsed with 2 µCi [3H]thymidine for the last 12 h.
Flow cytometry and Abs
A total of 5 x 105 cells was
incubated for 10 min in staining buffer (PBS containing 3% FCS and
0.01% NaN3) with Fc block
(anti-CD16/32, 2.4G2) and mouse Igs (10 µg/sample) on ice to
block FcR binding. Cells were then stained with the following
primary Abs: PE-conjugated anti-B220 (RA3-6B2), FITC-conjugated
anti-CD11c (HL3) and biotinylated anti-CD40 (3/23),
anti-CD80 (1G10), anti-I-Ab (25-9-17),
anti-CD100 (BMA-12), anti-CD72 (IOT 72.2), and
streptavidin-allophycocyanin. These Abs (except for anti-CD100 and
anti-CD72) and reagents were purchased from BD PharMingen.
Anti-CD100 was established previously (15), and
anti-CD72 was purchased from Immunotech (Marseille, France).
Data analysis was performed using FlowJo software (Treestar, San
Carlos, CA).
IL-12 production assay
IL-12 was quantitated after culturing DCs (1 x 106 cells/1 ml/24 well) for 72 h in the presence or absence of either anti-CD40 (3/23, 10 µg/ml), sCD100 (20 µg/ml), or anti-CD72 (IOT 72.2) (10 µg/ml). The IL-12 p40 was detected using a mouse IL-12 ELISA kit (R&D Systems).
Assays for in vivo induction of primary and memory T cells
Immature DCs (26, 27), prepared from normal C57BL/6 mice, were pulsed for 6 h with 10 µg/ml OVA (Sigma-Aldrich, St. Louis, MO). Cells were then dislodged and incubated for 12 h in the presence or absence of sCD100 (20 µg/ml) (15), control human IgG1 (10 µg/ml), and anti-CD40 (HM-40-3; 0.5 µg/ml). Following three PBS washes, DCs were resuspended in PBS for injection into the footpads of C57BL/6 mice (5 x 105 cells per footpad). Seven days after immunization with Ag-pulsed DCs, CD4+ T cells were prepared from the draining lymph nodes of the treated mice by MACS positive selection. A total of 1 x 105 T cells was stimulated for 72 h with various concentrations of OVA in the presence of irradiated (3000 rad) splenocytes (2 x 106 cells/well) derived from syngeneic mice in 96-well microtiter plates. Cells were pulsed with 2 µCi [3H]thymidine for the last 12 h. For the measurement of delayed-type hypersensitivity (DTH), mice were challenged 9 wk after left hind footpad immunization by the injection of 10 µg OVA in PBS into the right footpad and PBS alone into the left footpad. After 24 h, we recorded the increase in thickness of right vs left footpad, as described previously (27).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the involvement of CD100 in a pathological immune
responses, we used the MOG peptide-induced EAE model. As shown in Fig. 1
, s.c. immunization of
CD100+/+ mice with the MOG peptide, together with
pertussis toxin, induced severe encephalomyelitis associated with
rapidly ascending paralysis appearing at approximately day 10–14, as
described previously (25). In contrast, the development of
EAE was significantly reduced in CD100-/- mice,
and moreover, the affected CD100-/- mice
experienced a very mild disease course. To determine the mechanisms
responsible for the defective induction of EAE in
CD100-/- mice, CD4+ T
cells were prepared from the draining lymph nodes of immunized mice.
Following restimulation with the MOG peptide in vitro, Ag-specific T
cell responses, particularly generation of cytokine-producing effector
cells, were severely impaired in CD100-/- mice
(Fig. 2A). In addition, this
impairment could be reproduced after immunization with other protein
Ags, including OVA (Fig. 2B) and keyhole limpet hemocyanin
(16). These results indicate that a defect in generation
of Ag-specific effector T cells is at least one of the reasons for why
CD100-/- mice developed very mild EAE upon
immunization with MOG peptide, although CD100 may be also involved in
an effector phase. In the following experiments, we therefore focused
on how CD100 is involved in activation and differentiation of
Ag-specific T cells.
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To determine whether CD100-/- mice have
normal numbers of professional APCs, we first performed flow cytometric
analyses on splenic DCs in CD100-/- mice. As
shown in Fig. 3A, there were
no significant differences in either CD8-positive or CD8-negative
splenic DCs between CD100+/+ and
CD100-/- mice, suggesting that impaired T cell
priming in CD100-/- mice is due to the
defective T cell-APC interactions rather than the reduced number of DCs
in CD100-/- mice.
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B), but not on DCs cultured with medium alone (data not
shown). T cells express CD100 constitutively and abundantly (Fig. 3B). In addition, the expression of CD72 could be detected
not only on B cells, but also DCs (Fig. 3C). These findings
suggest that either T cell-derived or DC-derived CD100 may stimulate
DCs through CD72, as we previously reported for B cells
(15).
To elucidate how CD100 is involved in Ag-specific T cell activation, we
bred OVA-TCR Tg mice with CD100-/- BALB/c mice
to generate OVA-TCR Tg CD100-/- mice.
CD62Lbright CD4+ naive T
cells derived from either OVA-TCR Tg CD100-/-
or OVA-TCR Tg CD100+/+ mice were stimulated with
varying concentrations of an OVA-derived peptide and with
CD100+/+ or CD100-/-
BALB/c APCs. The absence of CD100 on either the T cells or APCs affects
the proliferative responses of OVA-TCR Tg T cells to an OVA-derived
peptide to some extent (Fig. 4A).
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- or IL-4-producing cells. Following a 7-day culture with
an OVA-derived peptide, CD4+ T cells were
restimulated with anti-CD3 and anti-CD28. We then measured the
concentrations of IFN- and IL-4 in the culture supernatants.
CD100+/+ OVA-TCR Tg T cells cultured with either
CD100+/+ or CD100-/- APCs
produced large amounts of IFN- and IL-4. In contrast,
CD100-/- OVA-TCR Tg T cells cultured with
either CD100+/+ or
CD100-/- APCs exhibited significantly reduced
production of these cytokines, indicating that surface expression of
CD100 on T cells is important for effective T cell differentiation into
functional effector cells (Fig. 4, B and C). Involvement of CD100 in DC allostimulation
We next examined whether CD100 contributes to the interactions
between T cells and DCs using a MLR. DCs generated from bone marrow
progenitors of CD100+/+ or
CD100-/- C57BL/6 mice by stimulating them with
GM-CSF were used to stimulate CD4+ T cells
isolated from CD100+/+ or
CD100-/- BALB/c mice. As shown in Fig. 5A, the absence of CD100 on
either the T cells or DCs substantially affects T cell proliferation.
The response was markedly reduced when both T cells and DCs lacked
CD100. This is consistent with a CD100 requirement for proliferative
responses of OVA-TCR Tg T cells (Fig. 4A). We next tested
the effects of sCD100 in a MLR using
CD100+/+CD4+ T cells as
responders and CD100+/+ or
CD100-/- DCs as stimulators. As shown in Fig. 5B, sCD100 significantly enhanced the MLR induced by both
CD100+/+ and CD100-/-
DCs. These results suggest that an optimal MLR requires the expression
of CD100 on T cells and on DCs. Indeed, activation by anti-CD40
enhances the expression of CD100 on DCs (Fig. 3B),
suggesting that DC-derived CD100 has some contribution in an autocrine
manner.
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C, both
CD100+/+ and CD100-/-
fixed mature DCs could induce similar levels of T cell proliferation in
CD100+/+ and CD100-/- T
cells when DCs were fully activated and then fixed. In particular, it
is noteworthy that there is no difference between responses of
CD100-/- T cells and
CD100+/+ T cells. Furthermore, sCD100 did not
enhance the MLR using CD100-/- T cells and
fixed mature CD100-/- DCs (Fig. 5D),
showing that sCD100 does not act on T cells. These results demonstrate
that CD100 acts directly on DCs, but not on T cells. Impaired expression of costimulatory molecules and IL-12 production in CD100-/- DCs
The ligation of CD40 on DCs and macrophages by CD40 ligand on the
surface of activated T cells induces expression of various
costimulatory molecules and cytokines such as CD80, CD86, and IL-12
(29, 30). We, therefore, examined the role of CD100 in the
CD40-induced expression of CD40, CD80, and I-A molecules on the cell
surface of DCs. Although a 14-h stimulation with anti-CD40
up-regulated the expression of CD40, CD80, and I-A on the surface of
CD100+/+ DCs, the expression of these molecules
was impaired in CD100-/- DCs (Fig. 6A). The effects of
anti-CD40 treatment were restored in
CD100-/- DCs by addition of sCD100, a treatment
that enhanced these changes in CD100+/+
DCs.
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-producing
Th1 effector cells (31). CD40-induced IL-12 production was
severely impaired in CD100-/- DCs. The addition
of sCD100 significantly enhanced CD40-induced IL-12 production in both
CD100+/+ and CD100-/- DCs
(Fig. 6B). These results suggest a critical role of CD100 in
the expression of immunoregulatory molecules during DC maturation.
Furthermore, agonistic CD72 mAb could mimic the effects of CD100 on
DCs, and not only rescued the defects of
CD100-/- DCs, but also enhanced IL-12
production of both CD100+/+ and
CD100-/- DCs (Fig. 6C), suggesting
that the effects of CD100 on DCs are also mediated through
CD72. Enhancement of Ag-specific primary and memory T cell responses by sCD100-treated Ag-pulsed DCs
We then analyzed the effect of CD100 on the ability of DC to
stimulate Ag-specific T cells in vivo. Bone marrow-derived DCs from
CD100+/+ mice on a C57BL/6 background were pulsed
with OVA protein for 6 h. After priming with OVA, DCs were treated
with sCD100, anti-CD40, or sCD100 plus anti-CD40. DCs were
injected s.c. into the hind footpads of syngeneic mice. We assessed the
immunogenicity of the injected DCs by in vitro restimulation of
Ag-specific T cells. DCs treated with sCD100 plus anti-CD40 induced
strong OVA-specific T cell responses, while DCs treated with
anti-CD40 alone induced relatively weak responses (Fig. 7A). No response was observed
in mice immunized with either untreated DCs or DCs treated with sCD100
alone. These results indicate that CD100 synergistically enhances the
ability of CD40-stimulated DCs to prime Ag-specific T cells.
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B). We did not observe a significant DTH
response in the mice injected with DCs that were pulsed with OVA and
stimulated with anti-CD40 alone. These results suggest that
sCD100 treatment enhances the capacity of Ag-pulsed DCs to induce both
primary T cell responses and Ag-specific T cell memory in
vivo. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C, CD72 is expressed on the
surface of splenic DCs, which is consistent with the previous findings
(22). Furthermore, agonistic CD72 mAb could mimic the
effects of CD100 on anti-CD40-stimulated DCs (Fig. 6C),
suggesting that the similar mechanism may be involved in CD100-induced
enhancement of DC activation. However, it still remains to be
determined whether CD72 is the only receptor for CD100 on DCs or
whether APCs express another receptor for CD100. Further studies will
be required to clarify the involvement of CD72 in CD40-mediated signals
in DCs.
Our present study demonstrates that CD100 expressed on either T cells
or DCs can contribute to the activation and maturation of DCs. Although
the development of DCs is not affected in
CD100-/- mice, anti-CD40-induced maturation
of CD100-/- DCs was defective in the context of
expression of costimulatory molecules and production of IL-12. It thus
appears that CD100 derived from DCs can also play a role in the
maturation of DCs in an autocrine manner. However, addition of sCD100
significantly enhanced CD40-induced IL-12 production and immunogenicity
of normal DCs, suggesting that exogenous CD100 probably derived from T
cells may be required for full activation of DCs. Indeed, the
expression of CD100 on the surface of T cells is much more abundant
than that on DCs (Fig. 3B). In our OVA-TCR Tg system, the
expression of CD100 on T cells, but not on APCs, was particularly
important for the differentiation of naive TCR-Tg T cells into
cytokine-producing effector cells (Fig. 4, B and
C). Hence, T cells may be a major source of CD100 in
physiological T cell-dependent immune responses through T cell-APC
interactions.
DCs play a role in linking the innate and adaptive immune responses, in which the innate immune system has been shown to be critically important in the activation of the adaptive immune system (32). In the innate immune system, microbial components stimulate DCs through Toll-like receptors (TLRs) (33). CD100-/- B cells are hyporesponsive to LPS, as shown in previous studies (16). LPS-induced IL-12 production was also affected in CD100-/- DCs (A. Kumanogoh, unpublished data), suggesting that CD100 may affect signals of TLR4 in an autocrine manner. Therefore, CD100 may play a role in shaping both the innate and adaptive immune responses by regulating the activation and maturation of DCs. It is of value to determine the involvement of CD100-CD72 interactions in TLR signals in DCs.
We have also shown that sCD100 can significantly enhance the ability of DCs to induce T cell priming and T cell memory. DCs have been used as adjuvant to enforce immunity against infection and tumors. Taken together with the fact that CD100-/- mice are resistant to EAE, our findings suggest that CD100 is a potential target not only for immunointervention of autoimmune diseases, but also for reinforcement of DC-based vaccination.
Besides CD100, several other semaphorins also have been shown to modify functions of immune cells, particularly monocytes. For instance, viral semaphorins, A39R encoded by vaccinia virus and AHVsema encoded by alcelaphine herpesvirus, have been shown to bind to its cellular receptor, virus-encoded semaphorin protein receptor/CD232/plexin-C1, and to induce robust responses in human monocytes (34, 35). In addition, a glycosylphosphatidylinositol-anchored semaphorin, CD108/Sema7A/Sema-K1, which may be a mammalian counterpart of AVHsema, has been demonstrated recently to bind to CD232/virus-encoded semaphorin protein receptor/plexin-C1 (19). Furthermore, Sema3A/H-SemIII, the representative semaphorin member identified as an axonal guidance factor, has been reported to inhibit monocyte migration (36). Although the physiological and pathological significance of these semaphorins has not yet been determined, it is possible that they may play important roles in cellular immune responses, as we have shown in this study for CD100. Future studies would not only clarify the functional significance of the semaphorin family in the immune system, but also open up a novel paradigm of the immunoregulatory semaphorin network.
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Acknowledgments |
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Footnotes |
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2 A.K. and K.S. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Hitoshi Kikutani, Department of Molecular Immunology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: kikutani{at}ragtime.biken.osaka-u.ac.jp
4 Abbreviations used in this paper: DC, dendritic cell; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; sCD100, soluble CD100; Tg, transgenic; TLR, Toll-like receptor.
Received for publication February 20, 2002. Accepted for publication May 22, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) is plotted, following the s.c.
immunization of mice with 100 µg MOG peptide and two i.v. injections
of pertussis toxin on days 0 and 2. Animals were then scored for
disease, as described previously (
;
CD100-/- T cells vs CD100+/+ DCs, •;
CD100-/- T cells vs CD100-/- DCs,
). B, Irradiated DCs, generated from
CD100+/+ and CD100-/- C57BL/6 mice, were
incubated with CD4+ T cells from CD100+/+
BALB/c mice with sCD100 or control human IgG1 (CD100+/+ DCs
plus IgG1, 
