Mol. Hum. Reprod. Advance Access originally published online on January 18, 2006
Molecular Human Reproduction 2005 11(12):865-870; doi:10.1093/molehr/gah246
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IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-
increase in normal pregnancy but decrease in spontaneous abortion
1Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, Toyama, 2Department of Infectious Disease Control and Clinical Immunology, Nihon University Advanced Medical Research Center, Tokyo, 3National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Aichi and 4COE 21st, Japan
5 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan. E-mail: s30saito{at}ms.toyama-mpu.ac.jp
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Abstract |
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Recent data demonstrated that CD4+CD25+ regulatory T (Treg) cells and an enzyme called indoleamine 2,3-dioxygenase (IDO) mediate maternal tolerance to the fetus. Interestingly, Treg cells express the CTLA-4 molecule on their surface, and B7 (CD80/86) ligation by CTLA-4 enhanced IDO activity of dendritic cells (DCs) and monocytes by the induction of interferon gamma (IFN-
) production. In this study, we studied the IDO expression on peripheral blood monocytes and decidual monocytes or DCs after treatment with CTLA-4/Fc fusion protein or IFN- using flow cytometry. IDO expressions on both peripheral blood DC and decidual DC and monocytes were up-regulated during normal pregnancy. On the other hand, both IDO expression on DC and monocytes after IFN- treatment or CTLA-4 treatment were decreased in spontaneous abortion cases. The expression of CD86 on peripheral blood and decidual monocytes and DC in spontaneous abortion cases was lower compared with those in normal pregnancy subjects. Also, IFN- production by decidual and peripheral blood mononuclear cells after CTLA-4/Fc treatment in spontaneous abortion cases was significantly lower than those in normal pregnancy subjects. These data suggest that CTLA-4 on Treg cells up-regulates IDO expression on decidual and peripheral blood DC and monocytes by the induction of IFN- production. Key words: CTLA-4/dendritic cell/IDO/pregnancy/regulatory T cell
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Introduction |
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A fetus is a semi-allograft to the maternal host, and T cells are aware of fetal alloantigens. Using T-cell receptor (TCR) transgenic mice, Tafuri et al. (1995)
demonstrated that maternal H-2Kb-specific CD8+ T cells were functionally tolerized by fetal H-2Kb alloantigen, but this state lasted only briefly after parturition. Supporting evidence was obtained from studies in which pregnant mice carrying syngeneic or allogeneic fetuses were treated with a pharmacologic inhibitor of an enzyme called indoleamine 2,3-dioxygenase (IDO) (Munn et al., 1998). IDO is expressed in specific populations of macrophages (Mô) and dendritic cells (DCs), giant trophoblasts in mice and extravillous trophoblasts and villous trophoblasts in humans (Munn et al., 1999, 2002; Hwu et al., 2000; Sedlmayr et al., 2002; Baban et al., 2004; Honig et al., 2004; Kudo et al., 2004). These findings suggest that immunosuppressive Mô and DC in decidua prevent maternal T-cell activation by depriving T cells of tryptophan. Serum tryptophan levels decrease from the first trimester of human pregnancy (Schrocksnadel et al., 1996), suggesting that tryptophan metabolism protects the allogenenic fetus in humans by inducing maternal tolerance, although IDO-deficient mice produce litters of normal sizes at normal rates compared with wild mice (Baban et al., 2004).
Recently, it has been reported that T-cell responses are regulated by CD4+CD25+ regulatory T (Treg) cells, and these Treg cells play a very important role in immunotolerance. CD4+CD25+ Treg cells express the CTLA-4 molecule on their surface, and CTLA-4 can enhance the IDO activity of DC and Mô (Grohmann et al., 2002; Fallarino et al., 2003). IDO induction in Mô or DC is one mechanism by which CD4+CD25+ Treg cells induce tolerance. Interestingly, recent data showed that CD4+CD25+ Treg cells are essential for the maintenance of allogeneic pregnancy in mice by the induction of maternal tolerance to fetal antigens (Aluvihare et al., 2004; Zenclussen et al., 2005). In human pregnancy, regulatory T cells increase in peripheral blood and decidua, and decidual CD4+CD25+ Treg cells express CTLA-4 on their surfaces (Heikkinen et al., 2004; Sasaki et al., 2004; Somerset et al., 2004). However, it has not been reported whether CTLA-4 can induce IDO protein expression in DC or monocytes during pregnancy.
IDO expression is also up-regulated by interferon gamma (IFN-) treatment (Taylor and Feng, 1991; Munn et al., 1999, 2004). IFN- is produced by decidual T cells and natural killer (NK) cells (Saito et al., 1993; Jokhi et al., 1994) and plays important roles in angiogenesis (Ashkar et al., 2000). In this study, we checked the IDO expression in peripheral blood and decidual monocytes or DC after treatment with CTLA-4 or IFN- in normal pregnancy subjects. We further compared these effects in spontaneous abortion cases with those in normal pregnant subjects. Our data showed that the IDO expression on DC and monocytes was up-regulated by IFN- or a soluble fusion protein of CTLA-4 and immunoglobulin Fc (CTLA-4/Fc) treatment during normal pregnancy, but both IDO expression on DC and monocytes with IFN- or CTLA-4/Fc treatment were decreased in spontaneous abortion cases, suggesting that CD4+CD25+ Treg cells and IFN- play important roles in the maintenance of pregnancy by the up-regulation of IDO expression.
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Materials and methods |
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Blood and tissue samples
Heparinized venous blood samples and decidual samples were obtained from induced abortion cases (n = 14; age 30.2 ± 4.5 years; gestational age at sampling 7.0 ± 1.3 weeks) and spontaneous abortion cases (n = 10) in the first trimester (age 31.5 ± 4.1 years; gestational age at sampling 7.2 ± 1.8 weeks). We obtained decidual samples and peripheral blood samples from the same patients. Blood samples were obtained from non-pregnant healthy women (n = 10; age 30.5 ± 3.1 years). Informed consent was obtained from all patients. Peripheral blood mononuclear cells were isolated by the standard Ficoll–Hypaque method. The decidual tissues were macroscopically separated from chorionic villi and then cut into small pieces using a razor blade and vigorously shaken for 2 min. These samples were then filtered through a 32 µm nylon mesh, and decidual mononuclear cells (leucocytes) were purified by the Ficoll–Hypaque method (Saito et al., 1993; Tsuda et al., 2002
). Decidual tissues were not enzymatically digested to prevent enzymatic treatment from affecting the fluorescence intensity of surface antigens. The yield of decidual leukocytes was 8.5 ± 3.0 x 106 cells. All of the sampling and use of tissues for this study were approved by the Toyama Medical and Pharmaceutical University Ethics Committees.
Culture system and IDO expression by flow cytometry
Isolated mononuclear cells (1 x 106/ml) were cultured using Roswell Park Memorial Institute (RPMI) 1640 medium (Sigma-Aldrich, Tokyo, Japan), supplemented with 10% heat-inactivated fetal calf serum in 12 well flat-bottomed plates for 24 h in the presence or absence of IFN- (R&D Systems, Minneapolis, MN, USA) or recombinant human CTLA-4/IgG Fc chimera (CTLA-4/Fc) (R&D Systems). For flow cytometric analysis, non-adherent and adherent cells were collected with a cell scraper after 24 h. Cells were first stained with a fluorescein isothiocyanate (FITC)-conjugated anti-CD14 mouse monoclonal antibody (mAb) (Becton Dickinson, San Diego, CA, USA) or FITC-conjugated lineage cocktail (CD3, CD14, CD16, CD19, CD20, CD56; Becton Dickinson) mAbs and Phycoerythrin (PE)-conjugated anti-HLA-DR mAb (Becton Dickinson). Then, to stain intracellular molecules, cells were treated with permeabilizing solution (Becton Dickinson). These cells were secondarily stained with a biotin-labelled anti-human IDO mAb (Takikawa et al., 1988), followed by streptavidin-PC5 (Beckman Coulter, Marseille, France). Isotype-matched mouse IgGs were used as a negative control. Flow cytometric analysis was performed on a fluorescence-activated cell sorter (FACS) Calibur using CellQuest software (Becton Dickinson). To analyse macrophages, a gate was set around the monocytes based on forward and side scatter (Figure 1, upper left) and then a gate was set on CD14+ cells (Figure 1, upper middle). After that, the population of intracellular IDO+ cells in CD14+ cells was calculated (Figure 1, upper right). To analyse DCs, a gate was set around the lymphocytes avoiding granulocytes (Figure 1, lower left) and a gate was set on lineage markers–/HLA-DR+ (Figure 1, lower middle). After that, the population of intracellular IDO+ cells in lineage markers–/HLA-DR+ cells was calculated (Figure 1, lower right).
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Cytokine quantitation
Culture supernatants were collected and analysed by the enzyme-linked immunosorbent assay (ELISA) method. An ELISA kit (ENDOGEN, Rockford, IL, USA) was used to quantify human IFN- in supernatants.
B7 molecule expression by flow cytometry
Isolated mononuclear cells were stained with FITC-conjugated anti-CD14 mAb or FITC-conjugated lineage cocktail mAbs and APC-conjugated anti-HLA-DR mAb (Becton Dickinson). Then, to stain B7 molecules, cells were also stained with a PE-conjugated anti-CD80 mAb (Becton Dickinson) and biotin-labelled anti-CD86 mAb (Becton Dickinson), followed by streptavidin-PC5.
Statistical analysis
The data were analysed by Friedmann test for paired samples or Mann–Whitney U-test for unpaired samples. P < 0.05 was considered significant.
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Results |
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IDO expression in peripheral blood and decidual monocytes and DCs
First, we examined the dose dependency of IFN-
or CTLA-4/Fc in the expression of IDO on peripheral blood monocytes and DCs of normal early pregnant women (n = 3). Treatment with IFN- or CTLA-4/Fc both increased IDO expression dose dependently and IDO expression reached a plateau at 1000 U/ml of IFN- and 10 µg/ml of CTLA-4/Fc (Figure 2). From these results, we decided to use 1000 U/ml of IFN- and 10 µg/ml of CTLA-4/Fc.
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As shown in Figure 3, under non-stimulated conditions, the expression of IDO in peripheral blood monocytes and DCs of non-pregnant subjects was very low. The expression rates in both peripheral blood monocytes and DCs of normal pregnancy subjects were significantly higher (P = 0.0077 and P = 0.0077, respectively) than those of non-pregnant subjects. Both IFN- and CTLA-4/Fc treatment enhanced the population of IDO-expressing peripheral blood monocytes and DCs of non-pregnant subjects. IFN- induced higher IDO expression in monocytes compared with that by CTLA-4/Fc, and CTLA-4/Fc induced higher IDO expression in DCs compared with that by IFN-. In spontaneous abortion cases, IDO expression of monocytes with IFN- treatment was significantly lower (P = 0.0139) compared with that in normal pregnancy subjects. CTLA-4/Fc-induced IDO expression in peripheral blood DCs of spontaneous abortion cases was significantly lower (P = 0.0192) than that in normal pregnancy subjects.
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IDO expression in non-stimulated decidual monocytes and DCs of spontaneous abortion cases were significantly lower (P = 0.0002 and P = 0.0029, respectively) than those in normal pregnant women (Figure 4). IDO expression in both decidual monocytes and DCs were significantly elevated by both IFN- and CTLA-4/Fc treatments. IFN- mainly augmented the expression of IDO in monocytes, whereas CTLA-4/Fc mainly augmented the expression in DCs. The response levels of decidual monocytes in spontaneous abortion cases with both IFN- and CTLA-4/Fc treatments were significantly lower (P = 0.0028 and P = 0.010, respectively) compared with those in normal pregnant subjects. The response levels of decidual DCs in spontaneous abortion cases by CTLA-4/Fc treatment were significantly lower (P = 0.0032) compared with those in normal pregnant subjects.
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IFN- production induced by CTLA-4/Fc
It has been reported that CTLA-4 induces IDO expression in DC through the induction of IFN- production (Grohmann et al., 2002; Munn et al., 2004). To investigate whether IDO expression by CTLA-4/Fc was through IFN- production, we checked the IFN- secretion by mononuclear cells treated by CTLA-4/Fc for 24 h.
As shown in Figures 5 and 6, CTLA-4/Fc induced IFN- secretion by both peripheral blood mononuclear cells and decidual leucocytes. CTLA-4/Fc-induced IFN- secretion by peripheral blood mononuclear cells in normal pregnancy subjects was significantly higher compared with those in non-pregnancy subjects (37.8 ± 13.8 pg/ml versus 18.0 ± 7.6 pg/ml, P = 0.0126). IFN- levels in spontaneous abortion cases were significantly lower compared with those in normal pregnancy subjects in both peripheral blood and decidua (26.0 ± 8.2 pg/ml versus 37.8 ± 13.8 pg/ml; P = 0.048 and 307.9 ± 237.6 versus 663.9 ± 277.4; P = 0.0052, respectively).
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The expression of B7 molecules in peripheral blood and decidual monocytes and DCs
It has been reported that engagement of B7-1/B7-2 (CD80/CD86) molecules on monocytes and DCs by CTLA-4/Fc activates a signalling pathway leading to the induction of IDO (Fallarino et al., 2003; Munn et al., 2004). We investigated whether the expression of IDO correlated with the expression of B7 molecules in peripheral and decidual monocytes and DCs.
As summarized in Table I, CD86 expression on peripheral blood monocytes and DCs in normal pregnancy subjects was significantly higher than those in non-pregnant subjects. CD86 expressions on peripheral blood monocytes, decidual monocytes and decidual DCs in spontaneous abortion cases were significantly lower compared with those in normal pregnancy subjects. On the other hand, CD80 expression on both peripheral blood and decidual monocytes and DCs in normal pregnancy subjects was the same as those in spontaneous abortion cases.
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Discussion |
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During pregnancy, the fetus is prevented from maternal immune rejection. Several specialized mechanisms have evolved to protect the semi-allograftic fetus from maternal immune attack. Studies in mice have suggested that the fetus is protected from immune rejection by maternal T cells by means of IDO-dependent depletion of tryptophan (Munn et al., 1998
). Recent data suggest that CD4+CD25+ Treg cells expand during pregnancy (Aluvihare et al., 2004; Heikkinen et al., 2004; Sasaki et al., 2004; Somerset et al., 2004; Zenclussen et al., 2005), and Treg cells mediate maternal tolerance to the fetus (Aluvihare et al., 2004). Treg cells constitutively express CTLA-4, and recently it was proposed that CTLA-4 induces IFN- production by DCs, which leads to the expression of IDO in DCs (Fallarino et al., 2003; Munn et al., 2004). Thus, the two mechanisms that induce maternal tolerance to the fetus have been linked.
We studied IDO expression on decidual and peripheral blood DCs and monocytes by CTLA-4/Fc using flow cytometry. CTLA-4/Fc treatment induced IDO expression in both decidual and peripheral blood DC and monocytes. The amplitude of IDO expression in DCs by CTLA-4/Fc was rather high compared with monocytes. On the other hand, the amplitude of IDO expression by IFN- in monocytes was rather high compared with DCs. Heikkinen et al. (2004) reported that IFN- induced the expression of IDO mRNA in peripheral blood CD14+ monocytes from pregnant women, but CTLA-4/Fc did not induce IDO mRNA in peripheral blood monocytes. Their data are inconsistent with our data. Our data showed that CTLA-4/Fc induced IDO expression in both peripheral blood and decidual CD14+ monocytes, although the expression rate of IDO was rather low compared to that with IFN- treatment. Post-transcriptional regulation of IDO may induce IDO protein expression in monocytes with CTLA-4/Fc treatment.
Binding of CTLA-4 and CD80/86 (B7 complex), followed by IFN- production by DCs, is required for the induction of IDO by Treg cells (Fallarino et al., 2003; Munn et al., 2004). These data showed that CD86 expression on peripheral blood monocytes and DCs and decidual DCs of spontaneous abortion cases was significantly decreased compared with normal pregnant subjects. These findings might explain why the CTLA-4/Fc-mediated IFN- secretion by decidual mononuclear cells in spontaneous abortion cases was significantly lower than that in normal pregnancy subjects (Figure 6). To clarify the mechanism of IDO expression in DCs and monocytes by CTLA-4/Fc, we examined the IFN- secretion level by CTLA-4/Fc-stimulated peripheral blood mononuclear cells and decidual mononuclear cells. The results showed that IFN- production by peripheral and decidual mononuclear cells after CTLA-4/Fc treatment in spontaneous abortion cases was significantly lower than those in normal pregnancy subjects, suggesting that IFN- production by the binding of CTLA-4 on Treg cells and CD80/86 expressing DC and monocytes could induce IDO expression in normal pregnancy subjects. However, in spontaneous abortion cases, suppressed IFN- production by the binding of CTLA-4 and decreased CD80/86 expressing DC and monocytes might reduce the IDO expression in DC and monocytes. It is well known that cytokine profiles in decidual T cells are in the Th2-dominant state (Piccinni et al., 1998; Saito et al., 1999; Tsuda et al., 2002; Kwak-Kim et al., 2003; Michimata et al., 2003), so the finding that CTLA-4/Fc treatment induces a large amount of IFN- secretion by decidual mononuclear cells is interesting. Decidual mononuclear cells contain IFN--producing NK cells, monocytes, T cells, NKT cells and DCs. Further study is needed to clarify which cells in the decidua produce IFN- after CTLA-4/Fc treatment.
Another important finding is that IDO expression in unstimulated decidual DCs and monocytes was up-regulated compared with those in peripheral blood. Human pregnancy decidua contains an abundance of Treg cells which express CTLA-4 at a high level (Heikkinen et al., 2004; Sasaki et al., 2004). These findings suggest that surface CTLA-4 on Treg in the decidua induces IDO expression in decidual DCs and monocytes preventing the maternal lymphocyte activation against the fetal allograft. It has been reported that the population of decidual CD4+CD25+ Treg cells and the surface CTLA expression on Treg cells are significantly lower in decidua from spontaneous abortion compared with those from specimens from induced abortion (Sasaki et al., 2004). In this study, IDO expressions in both decidual DCs and monocytes of spontaneous abortion cases were suppressed compared with those of normal pregnant subjects. Decreased CTLA-4-expressing Treg cells and suppressed IFN- production by CTLA-4 in the decidua of spontaneous abortion cases might induce the low expression of IDO in DCs and monocytes. Munn et al. (2002, 2004) reported that specific populations of DCs only express IDO with IFN- treatment. Specific populations of DCs and monocytes which could express the IDO enzyme with IFN- or CTLA-4-/Fc treatment might increase in the pregnancy decidua, and the population of these DCs and monocytes might decrease in spontaneous abortion.
In this study, we studied the expression of IDO as determined by flow cytometry. We should check whether these results are correlated with IDO activity or not. We studied the concentration of kynurenine, the major IDO degradation byproduct [using high-performance liquid chromatography (HPLC) analysis], in the conditioned media following in vitro culture of the peripheral blood mononuclear cells and decidual leukocytes. IDO-mediated tryptophan degradation in both peripheral and decidual leukocytes were up-regulated during pregnancy. On the other hand, both kynurenine concentration after IFN- treatment or CTLA-4 treatment were decreased in spontaneous abortion cases suggesting that IDO expression determined by flow cytometry is well correlated with the IDO enzyme activity.
In conclusion, our data showed that IDO expression in decidual monocytes and DCs by CTLA-4/Fc or IFN- treatment were increased in therapeutic abortion decidua but were decreased in spontaneous abortion. CTLA-4 on Treg cells might play a role in the maintenance of pregnancy by the induction of IDO in DCs and monocytes.
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Submitted on August 23, 2005; accepted on November 11, 2005.
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