Seminars in Immunopathology

, Volume 29, Issue 2, pp 115–122

Regulatory T cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance

Authors

    • Department of Obstetrics and GynecologyUniversity of Toyama
  • Arihiro Shiozaki
    • Department of Obstetrics and GynecologyUniversity of Toyama
  • Yasushi Sasaki
    • Department of Obstetrics and GynecologyUniversity of Toyama
  • Akitoshi Nakashima
    • Department of Obstetrics and GynecologyUniversity of Toyama
  • Tomoko Shima
    • Department of Obstetrics and GynecologyUniversity of Toyama
  • Mika Ito
    • Department of Obstetrics and GynecologyUniversity of Toyama
Review

DOI: 10.1007/s00281-007-0067-2

Cite this article as:
Saito, S., Shiozaki, A., Sasaki, Y. et al. Semin Immunopathol (2007) 29: 115. doi:10.1007/s00281-007-0067-2
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Abstract

In the early pregnancy decidua, lymphocytes express some activation markers on their surface, suggesting that maternal lymphocytes are activated and recognize the semiallograftic fetus. Therefore, the immunoregulation system must work to prevent fetus rejection. Recent data showed that parts of the immunoregulation system such as CD4+CD25+ regulatory T (Treg) cells, Th3 cells, Tr1 cells, regulatory NK cells, and a tryptophan-catabolizing enzyme, indolamine 2,3 deoxygenase, play very important roles in the maintenance of pregnancy. Not only Treg cells but also regulatory NK cells may inhibit maternal T cell or NK cell fetal attack.

Keywords

PregnancyRegulatory T cellRegulatory NK cellTh3 cellTr1 cell

Introduction

A fetus is a semiallograft; therefore, the process of pregnancy must include mechanisms to prevent allograft rejection. Some mechanisms for the maintenance of pregnancy have been proposed. For example, villous trophoblasts do not express classical major histocompatibility complex (MHC) class I and class II molecules in humans, although some MHC-class I molecules but not MHC-class II molecules are expressed on murine trophoblasts. On the other hand, extravillous trophoblasts in humans express MHC-class I molecules such as human histocompatibility leukocyte antigen (HLA)-C, HLA-E, and HLA-G, which are specific ligands for uterine natural killer (NK) cells [1, 2]. Effector functions of NK cells are finely regulated by a series of inhibitory and activating receptors. Decidual NK cells produce a number of cytokines that promote trophoblast proliferation and differentiation, as well as angiogenetic factors, when NK cells are activated by an activating signal [13]. On the other hand, NK cell cytotoxic activity against fetal cells or trophoblasts is regulated by inhibitory signals such as immunoglobulin-like transcripts 2 and killer-immunoglobulin-like receptors (KIR)2DL4, which recognize HLA-G or KIR2DL2, 3, and KIR2DL1, which recognizes HLA-C. Therefore, the balance between the activation system and regulation system in NK cells is important to maintain successful pregnancy.

Thus, the balance between immunostimulation and immunoregulation is very important in homeostasis. T cells can be classified into Th1 cells, which are involved in cellular immunity, Th2 cells, which are involved in humoral immunity, Th3 cells, which produce immunosuppressive cytokine transforming growth factor (TGF)-β, and Tr1 cells, which produce immunosuppressive cytokine interleukin (IL)-10, by their cytokine profiles (Fig. 1). The immune system is activated by Th1 or Th2 cells, and is regulated by Th3 or Tr1 cells. During pregnancy, the Th1/Th2 balance shifts to a Th2 predominant state, and Th3 cells and Tr1 cells regulate Th1 cell-induced rejection. Recent data showed that CD4+CD25+ regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance [4]. Furthermore, Treg cells play an essential role in the induction of tolerance to paternal antigens during pregnancy [58]. Recently, it has been clarified that there is a regulatory NK cell subset (Fig. 1) and that these cells may play an important role in the maintenance of pregnancy. In this review, the focus is on the balance between immunostimulation and regulation in T cells and NK cells during pregnancy.
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Fig. 1

Th1/Th2 paradigm develops into Th1/Th2/Th3/Tr1 paradigm and more. T cells are classified into CD4+ T cells and CD8+ T cells by their surface markers, and these cells are further classified into Th1 cells, Th2 cells, Tc1 cells, and Tc2 cells by their cytokine profile. The Th1 cells and Tc1 cells are involved in cellular immunity, and the Th2 and Tc2 cells are involved in humoral immunity. Recently, other cell types are reported Th3 cells, which produced TGF-β, Tr1 cells, which produce IL-10, and CD4+CD25+ regulatory T cells regulate overstimulation of type 1 immunity or type 2 immunity. NK cells also classified into NK1 and NK2 cells by their cytokine profile. Other cell types, NK3, NKr1, and regulatory NK cells have been reported recently

T cells and NK cells at the feto-maternal interface

The decidual immunological environment is quite different from that in peripheral blood. The population of T cells in early pregnancy decidua is about 10–15%, showing that T cells represent a minor population in the decidua. The major population in early pregnancy decidua is CD16-CD56bright NK cells, known as uterine NK (uNK) cells. Interestingly, both the numbers of T cell and NK cells increase at the decidua basalis (implantation site), while the population of T cells increases at the implantation site [8], suggesting that T cells accumulate at the feto-maternal interface and play an important role in the maintenance of pregnancy. Both decidual T cells and NK cells express activation markers such as CD69, CD25, CD122, and HLA-DR [9]. After activation, these cells produce a variety of cytokines. T cell immunity is classified into Th1 type immunity and Th2 immunity by the cytokine profile. Therefore, Th1-type cytokines or Th2-type cytokines are produced at the materno-fetal interface by these activated T cells and NK cells.

The Th1/Th2 balance in the peripheral blood of early pregnant women is controversial. Some reports showed a predominant Th2 status during pregnancy [10, 11], while other papers showed that the Th1/Th2 ratio did not change in the peripheral blood during early pregnancy [12, 13]. Systemic Th1/Th2 immunity in early pregnant women might not be very different from nonpregnant subjects. However, it is certain that predominant Th2-type immunity exists in early pregnancy decidua, especially at the implantation site [12, 14]. Regardless, immunoregulation should work at the materno-fetal interface to regulate immunostimulation so that the fetus is protected from activated maternal lymphocyte attack.

CD4+CD25+ Treg cells in alloantigen tolerance

Control of self-reactive T lymphocytes by Treg cells is essential for induction and maintenance of tolerance. These CD4+ T cells include thymus-derived CD4+CD25+ Treg cells, as well as distinct subjects of secondary suppressor T cells, including Th3 cells and Tr1 cells, in the periphery [4, 15]. Recent reports suggest that these CD4+CD25+ Treg cells play essential roles in alloantigen tolerance [16]. CD4+CD25+ Treg cells are involved in tolerance induction to allogeneic skin, pancreatic islets or heart transplants. The majority of such CD4+CD25+ Treg cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naïve T cells, and they are capable of recognizing both self- and nonself-antigens, thus enabling them to control various immune responses [4].

In the mouse, CD4+CD25+ T cells are homogeneous, and they exhibit a strong immunoregulatory function. However, in humans, CD4+CD25+ T cells are heterogeneous. A subset within CD4+CD25high or CD25bright cells exhibits a regulatory function, but the CD4+CD25low subset exhibits no such immunoregulatory function [17]. Other surface phenotypes such as CD122, CD132, glucocorticoid-induced tumor necrosis factor receptor superfamily-related gene, cytotoxic T lymphocyte antigen (CTLA)-4, programmed death-ligand 1, CD62, CD38, CD45, and CD103 are expressed on both human and murine CD4+CD25+ Treg cells [18]. The development and function of CD4+CD25+ Treg cells is controlled by Foxp3 [19]. A mutation of Foxp3 results in loss of CD4+CD25+ Treg cells and massive multiorgan autoimmunity in scurfy mice and immune dysregulation, polyendocrinopathy, enteropathy, X-linked patients. Furthermore, decreased Foxp3 expression in CD4+CD25+ Treg cells in various immune disorders such as graft-versus-host disease, myasthenia gravis, and multiple sclerosis has been reported. A large number (∼700 genes) of Foxp3-bound genes are up- or down-regulated in Foxp3+ T cells, suggesting that Foxp3 acts as both a transcription activator and repressor [20]. Foxp3 can cooperate in a DNA-binding complex with nuclear factor of activated T cell to regulate the transcription of several known target genes [21]. For example, Foxp3 down-regulates the transcription of Gpr171, Dusp6, Gadd45b, Jak2, IkBNS, ZAP70, Prpn22, Itk, Il2, Pou2af1, Myc, Tglf, Slfn2, and Ucp2 and up-regulates Ly6a, CD2, S100a6, and Irf8. Interestingly, mutation of PTPN22 has been reported in type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, and Grave’s disease. These mutations might inhibit the differentiation of CD4+CD25+ Treg cells, resulting in autoimmune disease. Recent data suggest that CD4+CD25+ Treg cells play an essential role in the maintenance of pregnancy.

CD4+CD25+ Treg cells in pregnancy

BALB/C nu/nu mice are T cell deficient. When BALB/C CD25 lymphocytes are transferred into BALB/C nu/nu female mice, they have conventional T cells but not CD4+CD25+ Treg cells. When these mice were mated with allogeneic C57BL/6 male mice, they showed spontaneous abortion. However, when these CD4+CD25+ Treg-deficient mice were mated with syngeneic BALB/C male mice, they had normal pregnancies [5], suggesting that allogeneic fetuses are rejected when CD4+CD25+ Treg cells are absent. The mating of CBA/J female (H2k) mice with DBA/2J males (H2d) provokes spontaneously high abortion rates. Adoptive transfer of CD4+CD25+ Treg cells from normal pregnant, not from nonpregnant, CBA/J mice prevents spontaneous abortion in this murine model, suggesting that alloantigen specific CD4+CD25+ Treg cells increase during allograftic pregnancy [8]. On the other hand, CD4+CD25+ Treg cells increase in syngeneic pregnant mice [5], suggesting that the expansion of CD4+CD25+ Treg cells is independent of exposure to paternal alloantigens. Further study is needed to prove the expansion of alloantigen specific CD4+CD25+ Treg cells during pregnancy. In humans, only CD4+CD25high or CD25bright T cells have an immunoregulation ability, and CD4+CD25dim T cells are recognized as activating T cells [17]. We firstly reported that CD4+CD25high Treg increased in the peripheral blood, and these Treg cells in early pregnant decidua further increased to three times the level found in the peripheral blood in humans [6]. Somerset et al. [7] reported that circulating CD4+CD25+ Treg cells increase during early pregnancy, peak during the second trimester, and then decline post partum. Interestingly, these increased peripheral and decidual CD4+CD25high Treg cell ratios decreased to nonpregnancy levels in miscarriage or recurrent miscarriage cases [6], suggesting that increased CD4+CD25high Treg cells are essential to maintain pregnancy. These CD4+CD25+ Treg cells dose-dependently suppress the DNA synthesis of conventional CD4+CD25 T cells [58]. There are at least three mechanisms by which CD4+CD25+ Treg cells induce immunoregulation (Fig. 2). The first mechanism is when CD4+CD25+ Treg cells induce immunoregulation by cell-to-cell interaction, although these immunoregulatory mechanisms have not yet been fully clarified. Membrane-bound TGF-β on CD4+CD25+ Treg cells has been reported to be the effecter molecule for immunoregulation [22], although this effect was not observed in TGF-β1 knockout mice [23]. Lag-3 contributes to the function of CD4+CD25+ Treg cells, but the reversal of suppression achieved by Lag-3 blockade is only modest [24]. Recent data suggest that galectin-1 is a key effecter of the CD4+CD25+ Treg cell immunoregulation [25]. Interestingly, the expression of galectin 1 is up-regulated in decidual NK cells and is regulated by estrogen and progesterone in the mouse uterus [26]. Sex steroid hormones may up-regulate galectin 1 on CD4+CD25+ Treg cells and up-regulate CD4+CD25+ Treg function. Indeed, estradiol (E2) induces Foxp3+expression [27] and enhanced suppression is detected when CD4+CD25+ Treg cells are pretreated with E2 in mice [28].
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Fig. 2

The mechanisms by which CD4+CD25+ Treg cells induce immunoregulation. CD4+CD25+ Treg cells induce immunoregulation by cell-to-cell interaction via membrane-bound TGF-β1, LAG-3, galectin 1, and CTLA-4. As a second mechanism, cytokines such as IL-10 and TGF-β produced by CD4+CD25+ Treg cells inhibit T cell activation

The second mechanism is when the cytokines such as TGF-β and IL-10 produced by CD4+CD25+ Treg cells ihhibit T cell activation (Fig. 2), while the third mechanism is when CTLA-4 expressed on CD4+CD25+ Treg cells induces indolamine 2, 3-dioxygenase (IDO) expression in dendritic cells (DCs) and macrophages (Mϕ; Fig. 2). This interaction induces interferon (IFN)-γ production by DCs resulting in IDO induction in DCs and Mϕ [29]. Tryptophan-catabolizing enzyme activity during pregnancy protects developing fetuses from the maternal immune response [30]. It has been reported that treatment with an IDO inhibitor in allogeneic pregnant mice induced abortion, although this inhibitor did not induce abortion in syngeneic pregnant mice [30].

We used a trans-well culture system to clarify which mechanism is important for immunoregulation by decidual CD4+CD25+ Treg cells, cell-to-cell interaction, or immunosuppressive cytokines [6]. Purified decidual CD4+CD25+ Treg cells and irradiated antigen-presenting cells (APCs) were seeded on the upper well, and conventional CD4+CD25 T cells and APCs were seeded on the lower well. Then, these cells were stimulated with an anti-CD3 monoclonal antibody. If immunosuppressive cytokines are key molecules that induce immunoregulation, CD4+CD25+ Treg cells should inhibit the DNA synthesis of conventional T cells in a trans-well culture system because immunoregulatory cytokines produced by CD4+CD25+ Treg cells easily pass through this membrane. Our data revealed that CD4+CD25+ Treg cells had no immunoregulatory ability in the trans-well system, suggesting that cell-to-cell contact between CD4+CD25+ Treg cells and conventional T cells is necessary for immunoregulation [6]. Recent data suggested that B7 (CD80/CD86) on macrophages and DCs bind CTLA-4 on CD4+CD25+ Treg cells and that this interaction induces IDO expression [29] (Fig. 2). CTLA-4 is usually located on lysosomes in CD4+CD25+ Treg cells. When CD4+CD25+ Treg cells recognize the antigen, lysosomal CTLA-4 quickly moves to the cell surface. The decidual CD4+CD25high Treg cells express surface CTLA-4 in normal pregnancy, although peripheral CD4+CD25high Treg cells do not express surface CTLA-4 in humans [6]. Interestingly, surface CTLA-4 expression on decidual CD4+CD25high Treg cells down-regulates in miscarriage cases [6]. This finding has two important implications. One is that decidual CD4+CD25high Treg cells may recognize fetal antigens and induce fetal antigen-specific tolerance at the materno-fetal interface. The other is that surface CTLA-4 on CD4+CD25high Treg cells may induce IDO expression in decidual DCs or macrophages. We studied whether CTLA-4 or IFN-γ induces IDO expression in DCs and macrophages [31]. Both IFN-γ and CTLA-4 augmented IDO expression in peripheral blood and decidual DC and macrophages, and these expressions in pregnant women were significantly higher than those in nonpregnant women. Interestingly, these IDO expressions decreased in miscarriage cases [31]. Not only the number of CD4+CD25high Treg cells but also the induction of IDO in DCs and macrophages by CTLA-4 decrease in miscarriage cases.

CD4+CD25+ Treg cells increase in regional lymph nodes of the uterus such as para-aortic lymph nodes and pelvic lymph nodes before implantation. CD4+CD25+ Treg cells have already increased on successful mating day 2 in mice [5, 8]. Implantation occurs on day 4.5 in mice, so increased CD4+CD25+ Treg cells in regional lymph nodes occurs before implantation, and these cells could play some roles in the maintenance of allogeneic pregnancy. Indeed, anti-CD25 monoclonal antibody treatment in an allogeneic pregnancy mice model on day 0 decreased the pregnant mice per total mated allogeneic pregnancy mice but not in syngeneic mice [5, 32]. This finding suggests that CD4+CD25+ Treg cells prevent fetal rejection at the implantation phase. In humans, Jasper et al. [33] reported reduced endometrial Foxp3 mRNA in unexplained infertility cases, but mRNAs encoding T cell transcription factors T-box expressed in T cell (T-bet) and GATA3, associated with differentiation of Th1 and Th2 cells, respectively, were unchanged. Previous studies showed that reduced CD4+CD25+ Treg cells before implantation induces fetal rejection. However, it has not been clarified whether reduced CD4+CD25+ Treg cells in the early pregnancy period induce fetal rejection or not. In our preliminary study, larger amounts of anti-CD25 monoclonal antibodies were needed to induce abortion in pregnant mice at days 4.5 and 7.5 of gestation. Early-stage embryos could be very susceptive to maternal immune cell attack. After successive implantation, the fetus has some defence mechanisms to prevent fetal rejection; therefore, a high amount of anti-CD25 antibodies might be needed to induce abortion. Recent data demonstrated that CD4+CD25+ Treg cell migration requires l-selectin expression [34]. Interestingly, up-regulation of l-selectin on circulating CD56bright NK cells during the periovulatory window (days 10–12) induced the promotion of CD56bright NK cells homing in on the uterus in humans [35]. l-Selectin expression on CD4+CD25+ Treg cells may up-regulate during the periovulatory period, and circulating CD4+CD25+ Treg cells might accumulate to the uterus in the implantation period.

Regulatory NK cells at the feto-maternal interface

The main population of decidual lymphocytes is CD16CD56bright NK cells (uNK cells), but the cytokine profile of uNK cells has not been clarified. We investigated the production of type 1 cytokines, IFN-γ, tumor necrosis factor α, type 2 cytokine, IL-4, IL-5, or IL-13, type 3 cytokine, TGF-β, and regulatory cytokine IL-10 from the peripheral blood and decidual CD56bright NK (uNK) cells and CD56dim (conventional) NK cells in early human pregnancy by flow cytometry [36]. Our data revealed that the cytokine profile in NK cells dramatically changed during pregnancy (Fig. 3) [36]. In the peripheral blood of nonpregnant subjects, the main population of CD56bright NK cells and CD56dim NK cells were IFN-γ-producing NK1 cells, which accounted for about 60% of the total, and other populations such as NK2, NK3, and NKr1 cell were very small (less than 2%; Fig. 3). After pregnancy, the IL-10-producing peripheral NKr1 cell population increased to more than 20%; these population rates were more than ten times higher compared to those in nonpregnant subjects, although the NK1 cell population did not decrease (Fig. 3). Another interesting finding was that the main population of decidual NK cells in normal pregnancy was TGF-β-producing NK3 cells, which accounted for about 20%, while the NK1 cell population dramatically fell to about 2% (Fig. 3). Therefore, the cytokine profile in decidual NK cells is quite different from that in peripheral blood NK cells. These findings suggest that NKr1 cells are the main player in the peripheral blood, while NK3 cells are the main player in the decidua, in immunoregulation during pregnancy. Our data reveal that the Th1/Th2 theory cannot be adapted to NK cells because the NK2 population is a very minor population. However, the balance between NK1 cells and NKr1 or NK3 cells might be adapted in NK cells. In the case of miscarriage, peripheral blood NKr1 cells and decidual NK3 cells decreased to nonpregnant levels, while peripheral blood and decidual NK1 cells increased (Fig. 3) [36]. This imbalance in the NK cell cytokine profile may cause fetal rejection, resulting in miscarriage. Recent data demonstrated that decidual NK cells produce a variety of cytokines that induce angiogenesis such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), TGF-β, angioporetin (Ang) 1, and Ang 2 [3, 4]. Decidual NK cells appear to be a prominent source of angiogenic growth factors within the placental bed [37]. Recent papers suggest that soluble fms-like tyrosine kinase 1, an anti-VEGF and PlGF, and soluble endoglin, an inhibitor of TGF-β, appear to be involved in the pathogenesis of pre-eclampsia [38]. Maladaption of the cytokine balance in NK cells may induce pre-eclampsia.
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Fig. 3

The population of NK1, NK2, NK3, and NKr1 cells during pregnancy. NK cells are classified into NK1, NK2, NK3, and NKr1 cells by their cytokine profile. NK cell population is quite different between the peripheral blood and decidua. NK cell populations are also different between normal pregnancy subjects and spontaneous abortion cases

MHC class I-specific tolerance and MHC class II-specific tolerance during pregnancy

CD4+CD25+ Treg cells play very important roles for induction of both MHC class I- and MHC class II-specific tolerance [4]. On the other hand, MHC class I-dependent reactivity in allograft tolerance is induced by NK cells but not by T cells NK T cells [39]. Maternal lymphocytes directly contact trophoblasts. MHC class II antigens and polymorphic MHC class I antigens such as HLA-A and HLA-B are not expressed on trophoblasts. Only HLA-C antigens are expressed on extravillous trophoblasts (EVT), while nonpolymorphic HLA-G and HLA-E are expressed on EVT. On this point, some researchers question whether MHC class I- or MHC class II-specific tolerance is present during pregnancy, but we detected anti-MHC class I and MHC class II antibodies in the serum of pregnant women suggesting that maternal lymphocytes recognize fetal MHC class I and class II antigens. It has been reported that MHC class II antigens, HLA-DR, and HLA-DQ are expressed on the endoplasmic reticulum in trophoblastic cell debris [40, 41]. Several grams of trophoblastic cell debris per day are released into the maternal circulation [42]. Fetus-derived lymphocytes are also present in maternal circulation [41]. These findings support the idea that MHC class I- and class II-specific tolerance play very important roles in the maintenance of pregnancy. We recently report regulatory NK cells in leukemic mice [43], and supportive data were also reported [44]. CD4+CD25+ Treg cells may induce MHC class I- and MHC class II-specific tolerance during pregnancy, while regulatory NK cells may induce MHC class I-specific tolerance during pregnancy.

Conclusion

The Th1/Th2 theory has now been developed to the Th1/Th2/Th3/Tr1 and CD4+CD25+ Treg paradigm (Fig. 1). NK cells can be classified into NK1 cells, NK2 cells, NK3 cells, and NKr1 cells by their cytokine profile (Fig. 1). We recently reported regulatory NK cells in leukemic mice [43]. Some authors have recently proposed the idea of regulatory NK cells [39, 44]. However, no specific marker for regulatory NK cells has been clarified. We should further examine the balance between the immunostimulation and immunoregulation systems at the feto-maternal interface. In the peripheral blood in early pregnancy subjects, the Th1/Th2 balance and NK1/NK2 balance are similar to those in nonpregnant subjects, but Tr1 cells, NKr1 cells, and CD4+CD25+ Treg cells increase (Fig. 3). These immunoregulation systems inhibit the overstimulation of type 1 or type 2 immunity. In the early pregnancy decidua, the Th1/Th2 balance and NK1/NK2 balance shift to a type 2 dominant state, and increased Th3 cells, NK3 cells and CD4+CD25+ Treg cells induce adequate tolerance to paternal antigens (Fig. 4).
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Fig. 4

Th1/Th2/Th3/Tr1 and NK1/NK2/NK3/NKr1 balance in nonpregnancy subjects, pregnancy subjects, and spontaneous abortion cases. In the immunostimulation system, Th1/Th2 and NK1/NK2 are balanced, and these immunostimulation systems are regulated by immunoregulation system such as Tr1, NKr1, Th3, NK3, and CD4+CD25+ Treg cells. These balances are different between peripheral blood lymphocytes and decidual lymphocytes

These balances are disturbed in miscarriage cases. The decidual Th1/Th2 balance and NK1/NK2 balance shift to a type 1 dominant state, and the immunoregulation system decreases to a nonpregnant level. In such an immunological environment, an allogeneic fetus could easily be rejected by the maternal immune system.

However, much remains to be done to fully understand how T cells and NK cells function in pregnancy.

Acknowledgment

This research was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan [Grant-in Aid for Scientific Research (B)-17390447 and (C)-18591797, and Grant-in-Aid for Exploratory Research 18659482] and the 21st Century COE Program.

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© Springer-Verlag 2007