Molecular Human Reproduction, Vol. 8, No. 7, 667-673,
July 2002
© 2002 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Expression of the interleukin-2 receptor 
(CD25) is selectively decreased on decidual CD4+ and CD8+ T lymphocytes in normal pregnancies
Department of Obstetrics and Gynecology, College of Medicine and Hospital, National Taiwan University, No. 7 Chung Shan South Road, Taipei 10063, Taiwan, Republic of China
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Abstract |
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In a previous study, we demonstrated that the proportion of activated T cells (CD69+CD3+ and HLA-DR+CD3+) is higher in the endometrium and decidua after the luteal phase and throughout early pregnancy compared with in the peripheral blood. However, there was no difference in the proportion of CD25+CD3+ lymphocytes between the endometrium and peripheral blood. In this study, we further verify that the levels of CD25 on CD4+ and CD8+ T lymphocytes are not increased in normal pregnancy, although the levels of CD69 and HLA-DR are markedly increased. We also elucidate that the amounts of all three activation molecules on local T lymphocytes are down-regulated in pregnancy compared with that during the luteal phase. Nevertheless, these decreases are significantly lessened in anembryonic pregnancies with both normal and abnormal karyotyping. However, in peripheral blood, the down-regulation of activation molecules levels in pregnancy is only demonstrated on CD4+ cells and for HLA-DR on CD8+ cells. Furthermore, dual activation marker analysis demonstrated that the expression of CD25 appears to be dissociated from CD69 and HLA-DR on the same decidual lymphocytes. Because IL-2R
plays a pivotal role in the development and propagation of functional T cells, its depressed expression may result in maternal tolerance of the fetal allograft. CD25/CD69/decidua/HLA-DR/T lymphocytes
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Introduction |
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During a normal pregnancy, allogenic fetal tissues are exposed to the maternal immune system. Normally, rejection reactions develop after allogenic recognition following the principle of transplantation immunology (Bugeon et al., 1992
). Although the immune system is functional in the uterus and the embryo expresses paternal major histocompatibility complex (MHC) molecules, the conceptus nevertheless escapes the deleterious effect of maternal rejection. The exact mechanisms involved in maternal tolerance of foreign fetal antigens during early pregnancy have not been fully explored, but may be due to local tolerance or even perhaps immune suppression after interactions between fetal antigens and the maternal immune system (Clark, 1991, 1999; Clark et al., 1999). The uterine mucosal lining, i.e. the endometrium, is transformed at the time of embryonic implantation into the decidua, which closely contacts fetal antigens. Both the decidua and trophoblast cells are known to play crucial roles in fetal survival. The utero-placental unit may suppress immune reactions through elaboration of soluble factors that suppress the cellular response or inhibit cytotoxic effector cells (van Vlasselaer and Vandeputte, 1984; Clark et al., 1985; Wang et al., 1987).
Activation molecules expressed on lymphocytes can be classified as early activation markers, such as CD69 (Testi et al., 1989) and CD25, and late activation markers, such as HLA-DR and very late antigen 1 (VLA1). Evidence of T cell activation in human endometrium has been reported with increased expression of CD69 and HLA-DR (Pace et al., 1989; Tabibzadeh, 1990a,b; Ho et al., 1996). However, it is interesting to note that the proportion of T lymphocytes with the CD25 antigen is selectively reduced in a normal pregnancy (Ho et al., 1996).
T cells must change from a resting to an activated state during immune responses and lead to de-novo synthesis of interleukin (IL)-2 and expression of IL-2 receptors (IL-2Rs) (Waldmann, 1986; Smith, 1988). There are three main IL-2 receptor subunits: IL-2R, IL-2Rß and IL-2R
(Waldmann, 1991). IL-2R, identified by the anti-CD25 monoclonal antibody, is a densely glycosylated structure with a molecular weight of 55 kDa (Leonard et al., 1984). Interaction of IL-2 and its receptors triggers cellular proliferation, culminating in the emergence of effector T cells that are required for the full expression of immune responses.
In this study, we further quantitatively measure and compare the molecular levels of activation markers on lymphocyte subpopulations in the endometrium and peripheral blood during the luteal phase, and in deciduae and peripheral blood of normal pregnancies and of anembryonic pregnancies with normal and abnormal karyotyping. The aim of the study was to elucidate the expression of T cell activation markers and to determine whether CD25 expression is dissociated from that of other activation markers in the same or different cells.
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Subjects
Twelve patients (aged 43.9 ± 3.4 years) who had undergone hysterectomies for benign reasons of non-endometrial pathology (mainly myoma uteri), 30 pregnant women (aged 33.0 ± 5.2 years) who had elective abortions of normal pregnancies due to multiparity, and 30 women (aged 33.4 ± 4.9 years) who had anembryonic pregnancies of between 6 and 10 weeks gestation were enrolled in the study with informed consent and under the approval of the ethics committee of our hospital. The women undergoing hysterectomies had regular menstruation before surgery. The pathological results of the hysterectomy specimens showed no evidence of infection or inflammation. All of them were in the luteal phase according to the last menstrual period, levels of progesterone and histological dating. An anembryonic pregnancy was identified by sonography which failed to show a fetal pole when the gestational sac was >25 mm. All three groups were matched by the number of previous pregnancies and by body mass index, but not by age. Although there was a 10 year difference in age between the hysterectomy and pregnant groups, according to our previous experience of lymphocyte subpopulations in endometrium and decidua of these women, the age difference does not affect the results, if they have regular menstrual cycles (data not shown).
Specimens
Endometrial tissues and venous blood obtained from hysterectomy patients were collected on the day of operation. Endometrial tissue was cut with a surgical knife immediately after the hysterectomy, minced with a scalpel, suspended in RPMI-1640 medium, and pressed gently through a 380 µm and then a 45.7 µm sieve as described previously (Ho et al., 1996). Decidual tissue and peripheral blood samples were taken from each pregnant woman at the time of abortion. The fetal chorionic villi were karyotyped when anembryonic pregnancies were diagnosed. In order to minimize contamination by blood, the decidual tissue was macroscopically separated from the chorionic villi, washed twice with Hank's balanced salt solution (HBSS: 1 g/l D-glucose, 0.35 g/l sodium bicarbonate, Phenol Red), cut into small pieces, washed twice again, and passed through a 1.9 mm mesh to remove the residual blood without enzymatic treatment. These samples were then filtered through a 45.7 µm stainless steel mesh to remove tissue debris. The filtered solution was layered over a Ficoll-Paque PLUS gradient and centrifuged for 45 min at 400 g. An enriched cell suspension was collected and washed twice with RPMI-1640 medium. The recovered cells were checked for viability with Trypan Blue and counted. Peripheral blood mononuclear cells (PBMCs) were also isolated by Ficoll-Paque PLUS sedimentation.
Immunophenotypic analysis
The following monoclonal antibody matchings (Becton Dickinson, San Jose, CA, USA) were used: anti-CD45 fluorescein isothiocyanate (FITC)/CD14 phycoerythrin (PE) (LeucoGATE), control 1/2a (1 FITC/2a PE), anti-CD3/CD19 (Leu-4 FITC/Leu-12 PE), anti-CD4/CD69/CD3 (Leu-3a FITC/L23 PE/Leu-4 PerCP), anti-CD8/CD69/CD3 (Leu-2a FITC/L23 PE/Leu-4 PerCP), anti-CD4/CD25/CD3 (Leu-3a FITC/CD25 PE/Leu-4 PerCP), anti-CD8/CD25/CD3 (Leu-2a FITC/CD25 PE/Leu-4 PerCP), anti-CD4/HLA-DR/CD3 (Leu-3a FITC/HLA-DR PE/Leu-4 PerCP) and anti-CD8/HLA-DR/CD3 (Leu-2a FITC/HLA-DR PE/Leu-4PerCP). Dual activation marker analysis of T lymphocytes were matched as anti-CD69/CD25/CD4, anti-CD69/CD25/CD8, anti-HLA-DR/CD25/CD4 and anti-HLA-DR/CD25/CD8.
Incubation with monoclonal antibodies was performed at 4°C for 30 min, and cells were then washed twice in phosphate-buffered saline containing 2% fetal calf serum and 0.1% sodium azide. Immunofluorescence and three-colour flow cytometric analyses were performed using a FACScan cytofluorimeter (Becton Dickinson) with computer interfacing to CellQuest software for full list mode data storage, recovery and analysis. Three-colour flow cytometry utilized an argon ion laser at 15 mW with 488 nm excitation. Triggering was set on the forward scatter channel, and the threshold was adjusted to exclude debris. LeucoGATE was used to measure the proportion of lymphocytes in the sample being studied without any scatter gates. Then, the gate was set around the lymphocytes (CD45+CD14-) to exclude other cells from analysis. The Simultest control (mouse IgG1 FITC + IgG2a PE) was used for background control. For each experiment, 5000 endometrial or decidual lymphocytes and 10 000 peripheral blood lymphocytes were evaluated.
Mitogenic activation of T cells in peripheral blood
We used phytohaemagglutinin (PHA) to activate peripheral blood mononuclear cells of 15 pregnant cases. Briefly, PHA (10 µg/ml) was added to 1 ml lymphocyte-enriched cell suspensions after collection, which then were incubated at 37°C in a 5% CO2-humidified incubator for 24 h. The trend and correlation of surface markers after full activation was further analysed by three-colour flow cytometry, as mentioned above.
Statistical analysis
All results are expressed as the mean ± SD. Statistical significance was tested using paired and non-paired Student's t-test. P < 0.05 was considered significant.
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Proportion of various activated T cells in luteal endometrium and decidua
There were increased percentages of CD69+CD4+, HLA-DR+CD4+, CD69+CD8+ and HLA-DR+CD8+ lymphocyte subpopulations in the endometrium and decidua compared with those in PBMC (Figure 1a,b
). However, in pregnancy, the proportion of decidual CD69+CD4+, HLA-DR+CD4+, and CD69+CD8+ lymphocytes markedly decreased as compared with those in the luteal endometrium. On the other hand, there was no significant change in the percentage of CD25+CD8+ lymphocytes between the decidua and peripheral blood and the proportion of CD25+CD4+ lymphocytes in the decidua had significantly decreased.
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, P < 0.05 versus the luteal phase.Expression of activation markers in the subpopulations of T cells of normal and anembryonic pregnancies
Among 30 aborti of anembryonic pregnancies, there were 12 cases with aberrant chromosomes, most of which were autosomal trisomies. There was no difference in the MFI distribution of activation markers on the decidual T lymphocytes between anembryonic pregnancies with normal and abnormal karyotypes (Table I
). Therefore we considered all cases of anembryonic pregnancies as a whole, irrespective of having normal or abnormal karyotypes. In a previous study (Ho et al., 1996) we found that there were increased CD69+CD3+ and HLA-DR+CD3+ lymphocyte subpopulations in the endometrium and decidua compared with those in PBMCs. In addition, a further increase in the proportion of CD69+CD3+ and HLA-DR+CD3+ lymphocytes was noted when anembryonic pregnancies occurred. Here we further demonstrate that the MFI of CD69 and HLA-DR on either CD4+ or CD8+ T cells is significantly higher in the luteal endometrium and deciduas than in PBMCs (Figure 2). In addition, we also note that these MFIs of the local lymphocyte subpopulation are significantly reduced in pregnancies compared with the luteal phase. These phenomena also appear in peripheral blood, except on CD69+CD8+ lymphocytes. However, the MFI for CD69 and HLA-DR of the local, not peripheral, lymphocyte subpopulation was not significantly reduced in anembryonic pregnancies, irrespective of their karyotypes (Figure 2).
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In this study, there was no statistical difference in the MFI of CD25 between PBMCs and decidual lymphocytes during a normal pregnancy (Figure 2
). Although the MFI of CD25 on local CD4+ lymphocytes was significantly reduced after pregnancy compared with that in the luteal endometrium, it was not reduced as much for anembryonic pregnancies (Figure 2). Nevertheless, there was no significant difference in the MFI of CD25 on CD8+ lymphocytes between normal and abnormal pregnancies. In short, the expression of CD25 on decidual T lymphocytes was dissociated from those of CD69 and HLA-DR, irrespective of cell proportion or molecular level.
Co-expression of activation markers on decidual CD4+ or CD8+T cells
To elucidate whether the dissociation of expression in activation markers occurs in different populations of T cells or on the same cell, we analysed dual activation markers for the combination of CD25 with CD69, and CD25 with HLA-DR on decidual CD4+ or CD8+ T cells. The results demonstrated that in pregnancy, most T cells expressed high levels of CD69 and HLA-DR, but not CD25, irrespective of whether they were CD4+ or CD8+ lymphocytes (Figure 3A). Furthermore, there was no difference observed in anembryonic pregnancies (data not shown). The expression of CD25 appeared to be dissociated from CD69 and HLA-DR for decidual T lymphocytes, irrespective of whether they were from normal or anembryonic pregnancies.
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Immunophenotyping of PBMCs from women with normal pregnancies after PHA stimulation
To distinguish whether the apparent dissociation of activation markers is due to systemic alterations of the immune system or to local effects, we used PHA to stimulate PBMCs from patients with normal pregnancies. After 24 h of activation, the MFIs of CD25, CD69 and HLA-DR had simultaneously increased in both CD4+ and CD8+ groups (Figure 3B
). The co-expression of CD25/CD69 and, to a lesser extent, of CD25/HLA-DR on the same T cells was demonstrated in the dual activation marker analysis. These results indicate that after activation, T cells derived from PBMCs of a normal pregnancy are able to simultaneously express CD25, CD69 and HLA-DR activation antigens. However, in the decidua of normal pregnancies, CD25 expression is selectively down-regulated. |
Discussion |
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In this study, an analysis of dual activation markers during normal pregnancy demonstrated that the activation profile of CD25 appears to be dissociated from that of CD69 and HLA-DR on the same cells. This means that CD25 expression is decreased or inhibited even though T cells are highly activated by the high expression of CD69 and HLA-DR molecules. Therefore, a selective down-regulation of IL-2 receptor expression appears to be present in decidual lymphocytes in normal pregnancy despite evidence of lymphocyte activation.
Although the fetus is a semi-allogenic transplantation during pregnancy, there is no rejection at the feto-maternal interface. Delineating the immune reactions there and understanding the nature of the peculiar regulation of the local immune system would contribute to the prevention of fetal rejection. As we know, immune rejection has been shown to require intact CD4+ helper T cells. Induction of IL-2 gene transcription and expression of IL-2R have also been shown to precede acute rejection (Bugeon et al., 1992). The interaction of allo-antigens with the T-cell antigen receptor complex (TCR) induces the expression of IL-2 and its homologous receptor on the T-cell surface, resulting in proliferation of these cells. IL-2 is a major T-cell growth factor for activating lymphocytes. The relevant role of IL-2 in the rejection episode has been further strengthened by inhibiting its production during tolerance induction (Josien et al., 1995), whereas the addition of recombinant IL-2 can restore this rejection (Dallman et al., 1991). Therefore, the involvement of the IL-2/IL-2R system marks a critical step in the activation of alloreactive T cells.
There are three IL-2 receptor subunits: IL-2R, IL-2Rß and IL-2R (Uchiyama et al., 1981; Sharon et al., 1986; Tsudo et al., 1986; Takeshita et al., 1992). Initial IL-2R-directed approaches to prevent allograft rejection were directed toward the IL-2R chain. IL-2 and IL-2R are not expressed by resting T cells, but they appear after activation by interaction with allo-antigens. The binding of IL-2 to these receptor subunits is important for clonal expansion and the persistent viability of activated T cells. Blocking inducible IL-2R with a monoclonal antibody (Taniguchi and Minami, 1993) or reducing the expression of the IL-2R subunit would inhibit the proliferation of allo-antigen-activated T cells, which would prevent the generation of cytotoxic T cells in the onset of the allogenic rejection process. On the basis of those studies, several new anti-IL-2R monoclonal antibodies were developed to provide positive effects on graft survival and reduced incidence of acute rejection in liver, heart, kidney and pancreas transplantation (Cantarovich et al., 1994; van Gelder et al., 1995; Langrehr et al., 1998).
However, IL-2 has been reported to have many useful roles during pregnancy. First, IL-2 induces the proliferation and natural killer (NK) activity of decidual large granular lymphocytes (King and Loke, 1990; Saito et al., 1993a). Under the influence of IL-2, large granular lymphocytes acquire the cytolytic potential that is characteristic of lymphokine-activated killer (LAK) cells and may have a role in the control of invasion of maternal tissue by placental trophoblasts (Ferry et al., 1990). In addition, IL-2 enhances the stimulatory actions of IL-1 and epidermal growth factor, which are essential for trophoblast growth (Wegmann, 1987). In this study, we have demonstrated that the proportion of activated T lymphocytes in the endometrium and decidua and the expression of their activation markers are increased compared with that in peripheral blood. This process may be hormone mediated. In particular, progesterone may play a core role in the activation of T lymphocytes at the feto-maternal interface. However, it is difficult to detect IL-2 in non-pathological human endometrium and decidua (Saito et al., 1993b; Jokhi et al., 1994, 1997; King et al., 1995; Lim et al., 1998). It appears that IL-2 is not produced anywhere in the normal implantation site. The cytokine IL-15 (Grabstein et al., 1994) has been shown to have a molecular structure and biological function similar to those of IL-2. It can cause proliferation and activate the entire lymphocyte subpopulation, including T and NK cells (Burton et al., 1994; Carson et al., 1994; Armitage et al., 1995). In addition, it has been demonstrated that IL-15 protein is localized to the glandular epithelium and stroma of human secretory phase endometrium and first trimester decidua (Kitaya et al., 2000; Okada et al., 2000). Therefore, it is possible that IL-15 might be an alternative to IL-2 as a potent effector of uterine lymphocytes (Giri et al., 1994; Kennedy and Park, 1996).
In our previous study (Ho et al., 1996), we demonstrated that CD69 and HLA-DR are highly expressed in the decidua, indicating that pregnancy is a state of both early and persistent activation. However, CD25 expression is down-regulated, especially that of CD4+ helper T lymphocytes. In this study, we further show that the expression of CD69 and HLA-DR on both CD4+ and CD8+ T cells also increases in the decidua. Nevertheless, the expression of CD25 on these T cells in the decidua is not increased. The reduced expression of CD25 on decidual lymphocytes may be a mechanism for suppressing the generation of potent LAK cells in the decidual environment, which would prevent the decidual lymphocytes from being too readily activated to kill the trophoblasts. In this way, we consider that the pregnancy may be under an immunosuppressive condition, and the fetus can therefore survive in the uterus without rejection, although closely surrounded by potentially hazardous decidual lymphocytes. However, this suppression is not complete, because decidual T cells still express high levels of CD69 and HLA-DR activation markers. This causes the decidual lymphocytes to secrete certain kinds of cytokines, in particular colony-stimulating factors, which may be important for trophoblast growth and feto-placental development (Wegmann, 1987).
The selective suppression of CD25 in the presence of other activation markers (CD69 and HLA-DR) on the lymphocytes has been reported in human primary breast carcinoma (Coventry et al., 1996) and in cervical cancer (Sheu et al., 1997, 2001a,b). This may represent the induction of tolerance within the local micro-environment. Some plausible mechanisms can explain this phenomenon. One possibility is that poor CD25 expression is due to intrinsic defects in T cells during the activation process. However, in this study the PBMCs of normal pregnant women could be stimulated by PHA to express all three activation markers, potentially excluding this hypothesis. Another possibility is that certain inhibitory mediators derived from the feto-placental unit or other decidual components alter the expression of CD25 on decidual lymphocytes. In an in-vitro study, Golander and colleagues clearly indicated that decidual tissue releases a soluble factor, which is a potent inhibitor of the mixed lymphocyte reaction, i.e. cell-mediated immunity (Golander et al., 1981). Furthermore, Daya et al. showed that decidua-associated suppresser cells elaborate soluble factors which have immunosuppressive properties through their ability to block IL-2 action (Daya et al., 1987). Similar immunosuppressive factors at the feto-maternal interface may lead to the observed phenomenon of down-regulated CD25 expression and may further lead to Th2/Tc2 induction in normal pregnancies (Ho et al., 2001), thus markedly suppressing T cell proliferation. Although the defective phosphorylation of the 
chain of TCR CD3 (Chaouat et al., 1997; Volumenie et al., 1997) and immunoregulation via OX-2 (CD200) (Clark et al., 2001a,b) might be the mechanisms of T cell anergy, the impairment of the IL-2 response, at least in part, may explain the protective effect, which prevents the fetus from being rejected by the mother.
Investigation of the activation marker profile of decidual lymphocytes in anembryonic pregnancies can provide valuable information concerning the functional change of decidual lymphocytes during a pathological situation. Decidual LAK cells are unlikely to be present in vivo in a normal pregnancy, but it is not known if they can develop in, or are responsible for, failed pregnancies. We demonstrated that the expression of CD25 on the CD4+ lymphocytes is markedly increased in anembryonic pregnancies compared with that in normal pregnancies. This altered phenotype may be indicative of an abnormal maternal immune response in an anembryonic pregnancy. With further increased expression of CD69 and HLA-DR, these decidual lymphocytes may be activated to kill the trophoblasts, potentially contributing to abortion. Furthermore, in this study we show that this response is the final common pathway for anembryonic pregnancies, regardless of the karyotype. This is similar to that found for the coagulation mechanism triggered by fgl2 prothrombinase, which also may represent a final common pathway for pregnancy termination (Clark et al., 2001a,b). Nevertheless, one is due to direct T cell cytotoxicity and the other to vascular injury in the maternal utero-placental blood vessels. However, changes in activation markers in anembryonic pregnancies may be the consequence rather than the cause of pregnancy failure. These changes may be induced by some unknown factors released following fetal rejection.
In conclusion, decreased expression of CD25 was found on activated CD4+ and CD8+ T lymphocytes derived from decidual tissue. Although high expression of CD69 and HLA-DR antigens may assist in the growth and development of the feto-placental unit, decidual T lymphocytes are functionally inhibited and lose the ability to undergo clonal proliferation and to induce cytotoxic activity, possibly due to down-regulated CD25 expression. The identification of decreased CD25 expression at the molecular level and the question of whether immunosuppressive factors are related to the predominance of T helper-2 cells at the feto-maternal interface are under further investigation. Nevertheless, this characteristic of CD25 expression on decidual T lymphocytes could be a plausible mechanism to facilitate fetal survival within a potentially hostile maternal environment.
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We thank Miss Shu-Ting Chang for her technical assistance. This study was supported partially by grants NSC-89-2314-B-002-171, NSC-89-2314-B-002-290 and NSC-90-2314-B-002-153 from the National Science Council of the Republic of China.
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1 To whom correspondence should be addressed. E-mail: hnho{at}ha.mc.ntu.edu.tw
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Submitted on September 14, 2001; resubmitted on December 28, 2001; accepted on April 8, 2002.
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