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Division of Immunology, Institute for Medical Science, Dokkyo University School of Medicine, Tochigi, Japan; Departments of
Immunology and
Rheumatology, Juntendo University School of Medicine, Tokyo, Japan;
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Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan;
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Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Tokyo, Japan; and
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Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115
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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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The B cell molecule CD40 and its ligand CD154 on the T cell are believed to play a central role in T cell-dependent B cell responses (6). CD40 is a member of the TNFR family, and CD154 belongs to the reciprocal family of TNF-related ligands and is expressed on activated CD4+ T cells. CD40-mediated signaling appears to be critical for B cell proliferation, isotype switching, germinal center formation, and memory B cell commitment. However, the concept of the central role of CD40 in T cell-dependent B cell responses may somewhat require modification because of previous contradictory finding that disruption of the interaction between CD40 and CD154 does not impair differentiation to Ab-producing cells. Patients with hyper-IgM immunodeficiency, in whom CD154 expression is deficient, usually have normal or elevated levels of IgM (7, 8, 9). These observations suggest that there might be CD154-independent and -specific signals that drive a B cell toward terminal differentiation to Ab-producing cells.
We previously demonstrated that the CD70/CD27 interaction, a ligand-receptor pair of the TNF/TNFR family, enhanced IgG production by human B cells (10, 11). CD70 is expressed on activated T cells, and its receptor CD27 is expressed by a subset of B cells. In contrast to the CD154/CD40 interaction, the CD70/CD27 interaction played a minor role in B cell proliferation and its major function was to contribute to the formation of Ig-producing cells (12), suggesting that the CD70/CD27 interaction may be more important in the induction of plasma cell differentiation at a time when the expansion phase induced by the CD154/CD40 interaction has already occurred.
Previous studies in the mouse have reported that the cross-linking of CD134 (OX40) ligand (CD134L),3 a relatively novel member of the TNF family, on B cells resulted in a dramatic B cell proliferation and Ig secretion (13). In addition, the CD134/CD134L interaction was found to be critical for the T cell-dependent IgG production and its interaction did not affect the germinal center formation nor memory B cell development (14). Although the cDNAs encoding human CD134 and CD134L have been cloned (15, 16, 17, 18), little is known about their roles in human T cell-dependent B cell responses. Recently, it was reported that ligation of CD134 on T cells increases IL-4 production by naive T cells and promotes their development into effector cells producing higher levels of the IL-4 (19).
It is well known that many cytokines derived from T cells affect B cell proliferation and differentiation (20). In particular, IL-4 appears to be involved in B cell growth and switch toward IgG4 and IgE. IL-2 is involved in the growth and differentiation of activated B cells but appears to have no effect on isotype switch. IL-10 acts as a cofactor for B cell proliferation and is particularly important in Ig secretion by inducing differentiation of B cells in the plasma cell pathway. IL-10 is also involved in isotype switch toward IgG1, IgG3, and IgA1.
In this study, to clarify the role of the CD134/CD134L interaction and regulatory mechanisms by TNF/TNFR family molecules in human T cell-dependent B cell responses, we have compared the effects of CD134L, CD27, and CD40 ligation on B cell Ig production and B cell proliferation in T cell-dependent and -independent systems. We demonstrate here that CD134/CD134L interactions induced an increase in B cell Ig production per cell but not B cell proliferation nor plasma cell generation in the presence of CD40, IL-4, or IL-10 stimulation. These results strongly suggest different and sequential roles of the CD134/CD134L, CD70/CD27, and CD154/CD40 interactions in human T cell-dependent B cell responses through cell-cell contacts and the cytokine network.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following mAbs were used in this study and have been described elsewhere: anti-CD3 (OKT-3, IgG2a), anti-CD14 (63D3, IgG1), anti-CD57 (HNK-1, IgM), anti-CD70 (2F11, IgG1), anti-CD134L (5A8; IgG1), and anti-CD154 (5c8, IgG2a) (11, 17, 21, 22). Purified anti-CD134, FITC-conjugated anti-CD3, anti-CD4, anti-CD8, anti-CD14, anti-CD38, PE-conjugated anti-CD19, anti-CD56, anti-CD154, anti-CD134, and isotype-matched control mAbs (mouse IgG1 and mouse IgG2a) were obtained from PharMingen (San Diego, CA). Recombinant human IL-4, IL-10, neutralizing anti-human IL-4 Ab, and anti-human IL-10 Ab were obtained from PharMingen.
Cell preparation
Human PBMCs were isolated from healthy donors by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density-gradient centrifugation. PBMCs were separated into the E rosette-positive and the E rosette-negative populations with 5% sheep erythrocytes. The E rosette-negative cells were depleted of monocytes by adherence to the plastic surface of culture dishes and further purified into B cells by complement (Cedarlane, Ontario, Canada) lysis with OKT-3, HNK-1, and 63D3 plus rat anti-mouse IgG1 mAb (PharMingen). The resultant B cell population was <2% CD14+, <1% CD3+, <2% CD57+, and >95% CD19+. All cultures were conducted in RPMI 1640 medium supplemented with 10% FCS, 2 mM L-glutamine, penicillin G (200U/ml), and gentamicine (10 µg/ml).
Transfectant cells
The murine pre-B cell line, 300-19 (23), was transfected by electroporation with the CD134 cDNA cloned into pMKITneo vector (pMKITneohgp34) (kindly gift from Dr. T. Uchiyama, Kyoto University, Kyoto, Japan). Transfected cells were selected by growth in medium with the neomycin analogue G418 (Life Technologies, Gaitherburg, MD), and cells with high-density CD134 expression were cloned by FACS. The CD70 cDNA-transfected cells, the CD154 cDNA-transfected cells, and the vector alone-transfected cells (mock) have been previously described (12).
Detection and quantification of IgG by ELISA
PBMCs (1 x 105/well) were cultured with pokeweed mitogen (PWM) (Life Technologies) at a final dilution of 1:100, and B cells (1 x 105/well) were cultured with Staphylococcus aureus Cowan I strain (SAC) (Sigma, St. Louis, MO) at a final concentration of 1:10,000 (v/v) and IL-2 (50 U/ml) in 96-well round-bottom plates in 0.2 ml of culture medium for 10 days at 37°C in a humidified atmosphere with 5% CO2. Various amounts of mAb (0.5, 1, and 2 µg/ml) or irradiated (10,000 rad) transfected cells (5 x 103, 1 x 104, and 2 x 104 per well) with or without IL-4 (100 U/ml) or IL-10 (100 ng/ml) were added at the beginning of the experiment. In some experiments, CD134-transfected cells were pretreated with anti-CD134 mAb at 5 µg/ml for 30 min on ice and then added to the cultures after extensive washing. The culture supernatants were harvested and added to goat anti-human Ig (Southern Biotechnology Associates, Birmingham, AL)-coated 96-well flat-bottom ELISA plates overnight. After discarding supernatants and washing with Tween 20 PBS, the bound human IgG was detected with HRP-labeled goat anti-human IgG at a dilution of 1:2000 followed by addition of p-nitophenyl phosphate substrate (Sigma), and the amount of IgG present was assessed by spectrophotometric analysis at 490 nm.
B cell proliferation assay
B cells (105/well) were cultured with SAC (0.01%) and IL-2 (50U/ml) in 96-well round-bottom plates in 0.2 ml of culture medium for 4 days at 37°C in a humidified atmosphere with 5% CO2. Various amounts of irradiated (10,000 rad) transfectant cells with or without IL-4 (100 U/ml) or IL-10 (100 ng/ml) were added at the beginning of the experiment. After 3 days, the cultures were pulsed with 1 µCi/well of [3H]thymidine. Eighteen hours later, the cells were harvested, and [3H]thymidine incorporation was measured in a liquid scintillation beta counter (Wallac, Turuku, Finland).
Flow cytometric analysis
Flow cytometric analysis was performed using FACScalibur (Becton Dickinson, San Jose, CA), and data were processed using the CellQuest program (Becton Dickinson). In some experiments, FITC-conjugated goat anti-mouse Ig (Southern Biotechnology Associates) was used as a second Ab in this study. Isotype-matched mouse IgG control was used throughout the studies and always reacted with <5% of the cells.
Statistical analysis
The paired t test was used to determine statistical significance of the data. Values of p < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent studies in the mouse have demonstrated that CD134/CD134L
interactions play an essential role in T cell-dependent Ab production
(13, 14). In vitro, cross-linking of CD134L induced B cell
proliferation and differentiation. In vivo, blockage of CD134/CD134L
interaction by means of a polyclonal anti-CD134 Ab strongly
inhibited primary and secondary IgG, but not the IgM Ab response to T
cell-dependent Ag, suggesting that murine CD134/CD134L interaction is
crucial importance for the terminal differentiation of activated B
cells into plasma cells producing high levels of Ig. First, to
investigate whether CD134/CD134L interaction is also involved in human
T cell-dependent B cell responses, we examined the effect of
anti-CD134L mAb on a T cell-dependent, PWM-driven B cell Ig
synthesis system. The addition of anti-CD134L mAb caused a
significant inhibition of IgG production in a dose-dependent manner
(Fig. 1
A). Consistent with our
and other reports (6, 11), anti-CD70 mAb and
anti-CD154 mAb also inhibited IgG production and mixture of these
Abs blocked IgG production by 
90% (Fig. 1B). These
results strongly suggest that CD134/CD134L interactions are involved in
human T cell-dependent B cell Ig production.
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In the previous mouse study, it was shown that activated B cells,
such as peritoneal B cells expressing high levels of MHC class II Ag or
B cells in the periarteriolar lymphoid sheath following immunization
with specific Ag, express CD134L (24). Therefore, we
examined the expression of CD134 and CD134L in human PBMCs. We found
that PWM stimulation preferentially induced CD134 on T cells and CD134L
on B cells (Fig. 2).
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To further clarify the role of CD134/CD134L interactions in B cell
activation, we undertook a series of experiments examining the effect
of CD134- and mock-transfected cells on Ig production in the T
cell-dependent, PWM-driven system. In our previous studies
(10, 11, 12), CD70-transfected cells but not CD154-transfected
cells enhanced B cell Ig production in the T cell-dependent system.
When CD134-transfected cells were added to PBMCs stimulated with PWM,
IgG production was enhanced in a dose-dependent fashion as well as upon
addition of CD70-transfected cells, whereas CD154- and mock-transfected
cells had no effect (Fig. 3A).
Moreover, the enhancing effect of CD134-transfected cells on IgG
production could be blocked by pretreatment of these cells with
anti-CD134 mAb (Fig. 3B). These results clearly indicate
that enhancement of IgG production by CD134-transfected cells was
specifically mediated by CD134/CD134L interactions.
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To determine whether CD134-transfected cells interacted primarily
with CD134L+ B cells and resulted in induction of
IgG production, we examined the effects of these transfected cells in a
T cell-independent, SAC/IL-2-driven B cell activation system. As shown
in Fig. 4, addition of CD134-transfected
cells in the absence of T cells resulted in little if any enhancement
of B cell IgG production and B cell proliferation, whereas
CD154-transfected cells enhanced B cell proliferation but not IgG
production, and CD70-transfected cells moderately enhanced both,
consistent with our previous studies (10, 11, 12).
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A). Interestingly, this
enhancement of IgG production by CD134-transfected cells was also
observed in the presence of T cell cytokines such as IL-4 and IL-10
instead of CD154-transfected cells. IL-4 or IL-10 by itself slightly
enhanced IgG production in the present SAC/IL-2 system.
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B). To examine whether CD40 stimulation or T cell
cytokines up-regulate the CD134L expression on the B cell, we
cocultured B cells with CD154-transfected cells, IL-4, or IL-10 in the
presence of SAC/IL-2. No significant change in CD134L expression was
observed in each culture condition (data not shown). Next, to confirm
that IL-4 or IL-10 is required for CD134L-induced B cell IgG
production, we examined the effect of neutralizing anti-IL-4 or
IL-10 Ab on T cell-dependent, PWM-driven B cell IgG production in the
presence of CD134-transfected cells. The addition of neutralizing
anti-IL-4 or IL-10 Ab abolished the enhancement of IgG production
by CD134 transfectant cells (data not shown). These results strongly suggest that CD134L engagement can directly mediate a signal for B cell IgG production in the presence of CD154-transfected cells, IL-4, or IL-10, which is not accounted for by the increase in B cell proliferation nor up-regulation of CD134L on B cells.
Increase in IgG production per cell by CD134L engagement
Finally, we decided to examine whether the enhancement of IgG
production by CD134L engagement could have been due to increased Ig
production per cell or to production by a larger portion of the plasma
cells. We stained with anti-CD19 and anti-CD38 mAbs B cells
cocultured with CD134-transfected cells together with or without
CD154-transfected cells, IL-4, or IL-10 in the presence of SAC/IL-2. As
shown in Fig. 6, the presence of
CD134-transfected cells with CD154-transfected cells, IL-4, or IL-10
showed an almost same percentage of cells with a plasma cell phenotype
(CD19-CD38+) as that in
culture without CD134-transfected cells. To confirm the increased per
cell Ig production by CD134L engagement, we measured the number of
Ig-producing cells in the culture with CD134L engagement. As shown in
Table I, the addition of
CD134-transfected cells showed an almost equal number or a slight
increase in the number of viable B cells, thus indicating only a slight
increase of CD19-CD38+
plasma cells. Therefore, when calculated, per cell IgG production was
significantly higher in the presence of CD154-transfected cells, IL-4,
or IL-10 after CD134L engagement. These results clearly indicate that
an increased Ig production rate per cell is responsible for the
observed enhancing effect of CD134L engagement on IgG production.
Supporting this result, CD134-transfected cells together with
CD70-transfected cells enhanced B cell IgG production induced by
CD134-transfected cells alone or CD70-transfected cells alone in the
presence of SAC/IL-2 plus IL-4 or IL-10 (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In our previous and present studies, CD40 engagement induced B cell proliferation but not Ig production, and CD27 engagement induced moderate B cell proliferation and Ig production (6, 10, 11, 12). CD134L engagement induced Ig production but not B cell proliferation in the presence of additional stimuli such as CD40 ligation, IL-4, or IL-10. We have previously reported that the CD70/CD27 interaction may be more important in the induction of plasma cell differentiation at a time when the expansion phase induced by the CD154/CD40 interaction has already occurred (12). B cells express CD134L only upon activation, while CD40 and CD27 are expressed by resting and activated B cells. In contrast, CD134, CD154, and CD70 are only expressed on activated T cells. Thus, it is more likely that CD154/CD40, CD70/CD27, and CD134/CD134L interactions exhibit their functions in the relatively early, intermediate, and late phases of T cell-dependent B cell responses, respectively. In fact, the additive and sequential expression of CD154 and CD70/CD134 on T cells after activation appears to correlate with B cell expansion and plasma cell generation/Ig production, respectively, in the course of T cell-dependent B cell responses. It should be noted that CD134/CD134L interactions may play a critical role in the regulation of sufficient and effective Ig production because both CD134 and CD134L are expressed on T and B cells only after activation, and CD134L engagement appeared to exhibit its enhancing effect on B cell IgG production only when additional stimuli are provided.
Early stimulatory signals derived from CD40 ligation, IL-4, or IL-10 seem to be required for human B cell Ig production induced by CD134L engagement. This notion was supported by the finding that neutralizing anti-IL-4 or IL-10 Ab reduced Ig production enhanced by CD134L engagement. Previous studies have shown that the expression of CD154 and the production of several cytokines in vivo reach their maximum in the same time period in the early phase of B cell responses (25). IL-4 is reported to inhibit the differentiation but not the proliferation of IL-2-dependent primary Ag-specific B cell responses (26, 27). IL-10 synergizes with IL-2 for B cell Ig production (28). CD134L-mediated signal alone appeared to be insufficient to induce high level of B cell Ig production in the absence of additional signal(s) provided by CD40 or T cell cytokines even though B cell receptor is cross-linked with SAC and IL-2 is provided. CD40 signal or T cell cytokine stimulation is required to couple the CD134L signal to the signal pathway for production of higher levels of Ig in addition to basal Ig production by SAC plus IL-2. It is possible that CD40 ligation induces B cells to secrete IL-10 (29). It was demonstrated that resting B cells differ from activated B cells in their stimulation requirements for terminal differentiation (30). Resting B cells need activated T cell contact with Th2-type cytokines such as IL-4 and IL-10 to initiate Ig production. Activated B cells differentiate by activated T cell contact with Th1-like cytokine such as IL-2. B cells responding to CD134L stimulation might be a distinct subpopulation because 10–30% of B cells can express CD134L after activation.
At present, the precise mechanisms of synergistic effect of
CD134/CD134L interaction and CD40 ligation, IL-4, or IL-10 on B cell Ig
production is still unknown. CD134/CD134L interactions may require
Th2-type cytokines such as IL-4 and IL-10 for exhibiting its activity
of B cell Ig production. Recent study in the mouse has shown that CD134
engagement on T cells induced IL-4 expression and inhibited IFN-
expression, resulting in Th2 immune responses (31). In
humans, ligation of CD134 also increased IL-4 production by naive T
cells and promoted their development into effector cells producing
higher levels of the Th2 cytokines (19). Taken together,
CD134/CD134L interactions appear to provide a costimulatory signal for
the Th2 immune responses in a two-signaling system, with CD134L on
activated B cells having the potential to costimulate T cells, and
CD134 on activated T cells providing a signal for B cell Ig production.
It is possible that CD134L engagement increases responsiveness to IL-4
or IL-10. The precise biological nature of CD134L-mediated B cell
activation and its signaling events remain to be clarified in future
studies.
The mechanism by which CD134L engagement induced Ig production is apparently different from that of CD27 engagement: Ig production by CD27 engagement was mainly due to an increased number of Ig-producing cells, while that by CD134L engagement was due to an increased per cell production rate. This notion was supported by the fact that addition of both CD70- and CD134-transfected cells showed the additive effect on B cell IgG production. Thus, CD70/CD27 and CD134/CD134L interactions might be a T cell-dependent mechanism stimulating B cells to produce large amount of Ab in the immune responses at the relatively early and late phase, respectively. Because it has been recently reported that CD27 is also a marker for human memory B cells (32, 33), the CD134/CD134L interaction may be more important in the sufficient and effective Ab production after plasma cells were generated from memory B cells by CD70/CD27 interactions. We have previously reported that the extent of T cell-dependent B cell responses may be regulated by the ratio of CD27+ T cells and CD70+ T cells and that CD27+ T cells may serve as regulatory T cells (11). Because only CD27 is expressed on T cells among these molecules (CD40, CD27, and CD134L) expressed on B cells, these findings elucidate that the CD70/CD27 interaction may play a pivotal role in regulating T cell-dependent B cell Ig production.
The ability of human CD134/CD134L interaction to mediate a signal for B cell Ig production but not B cell proliferation is of considerable interest because murine CD134/CD134L interaction is reported to play an important role both in B cell proliferation and Ig production (13, 14). In addition, Ig production by murine CD134/CD134L interactions appears to be independent on T cell-derived cytokines (13), while human CD134/CD134L interactions require them. CD27 expression was not observed on resting and activated B cells in the mouse (34), and no overt impediment in T cell-dependent B cell responses could be observed in CD27-deficient mice (J. Borst, unpublished observations). Thus, there might be a difference in regulatory mechanisms of T cell-dependent B cell responses by TNF/TNFR family molecules between humans and mice.
In summary, these observations fit our current models of the kinetic
dynamics of human B cell terminal differentiation during the response
to T cell-dependent Ags, which is summarized in Fig. 7. CD154/CD40 interaction is first
required to stimulate the clonal expansion of Ag-specific B cells and
induce Ig isotype switching. In the second step, CD70/CD27 interaction
induces further B cell proliferation to lesser extent and induces
plasma cell generation. In the third step, CD134/CD134L interaction
enhances Ab production by plasma cells in the presence of IL-4 or
IL-10. These TNF/TNFR family molecules appear to coordinate T
cell-dependent B cell responses through cell-cell contacts and the
cytokine network. At the present, it is not clear whether CD27 and
CD134L engagement induce Ig class switching. It is possible that the
enhanced IgG production is due to an increase IgG production by already
isotype-switched cells. Nagumo et al. have reported that CD27
engagement augmented IgE production in cooperation with IL-4 and CD40
signal (35), in which CD70/CD27 interactions do not appear
to induce IgE class switching. In addition, Morio et al. have
demonstrated that CD27 did not interact with Ku, which is required for
Ig class switching (36). Our present data are not only
important to clarify the exact steps in T cell-dependent B cell
responses, but also are of interest in considering the mechanisms of
autoantibody production and hypergammaglobulinemia observed in
autoimmune diseases such as systemic lupus erythematosus.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Tetsuji Kobata, Division of Immunology, Institute for Medical Science, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan.
3 Abbreviations used in this paper: CD134L, CD134 ligand; PWM, pokeweed mitogen; SAC, staphylococcus aureus Cowan I strain.
Received for publication September 20, 1999. Accepted for publication February 9, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells. J. Exp. Med. 179:819.This article has been cited by other articles:
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S. Jacquot, L. Macon-Lemaitre, E. Paris, T. Kobata, Y. Tanaka, C. Morimoto, S. F. Schlossman, and F. Tron B cell co-receptors regulating T cell-dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immuno-compromised patients Int. Immunol., July 1, 2001; 13(7): 871 - 876. [Abstract] [Full Text] [PDF]
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