Progesterone Induced Blocking Factor Seen in Pregnancy Lymphocytes Soon After Implantation

PROBLEM: The immunomodulatory effect of progesterone (P) in pregnancy manifested via a protein named the P-induced blocking factor (PIBF) was previously reported. The goal of this study was to measure and compare the PIBF expression on lymphocytes between pregnant and non-pregnant women especially in early pregnancy. METHODS: PIBF expression was determined by immunocytochemistry using a PIBF-specific polyclonal antibody. Levels were assessed during the mid-cycle, luteal phase, and first trimester of pregnancy. RESULTS: PIBF expression was found in 24.9% of mid-cycle sera, 49% of luteal phase sera of women who failed to conceive, and 75% of luteal phase sera of women who conceived. CONCLUSIONS: These data indicate that the percentage of PIBF expressing lymphocytes increases as a result of pregnancy and that the stimulus for PIBF induction occurs soon after implantation. These data support the concept that PIBF may play an important role in early implantation possibly by inhibiting the destructive function of natural killer lymphocytes.     

Lymphocyte Immunotherapy (LI) Increases Serum Levels of Progesterone Induced Blocking Factor (PIBF)

PROBLEM: To determine if allogenic stimulation from leukocyte immunization (LI) can increase the production of an immunomodulatory protein called progesterone induced blocking factor (PIBF) by CD8+ T-lymphocytes. METHOD: The study group consisted of 35 women, 29 who failed to conceive after repeated embryo transfers (ETs) and six with recurrent spontaneous abortion (RSA). The women underwent LI using the male partner's blood as the source of leukocytes. Progesterone induced blocking factor was measured pre- and post-LI with an immunocytochemistry method using a PIBF-specific polyclonal antibody. RESULTS: The mean percentage of lymphocytes expressing PIBF, as well as the percentage of cases whose PIBF level increased to 1% or more, was significantly higher post-LI. Similarly post-LI, there was a significantly lower percentage of zero PIBF levels. CONCLUSIONS: Leukocyte immunization causes an increase in PIBF in many cases. Possibly the improved pregnancy outcome in immunized patients with RSA or previous failure to conceive with in vitro fertilization may be partially or possibly completely explained by its stimulatory effect on PIBF.     

Progesterone as an immunomodulator

In the presence of progesterone, lymphocytes of healthy pregnant women produce a 34-kDa protein, which, because of its immunomodulatory effects has been called progesterone induced blocking factor (PIBF). PIBF is a secreted molecule and thus appears in biological fluids. Urinary PIBF concentrations in healthy pregnant women are significantly higher than in recurrent aborters, or in women showing clinical symptoms of threatened abortion. Recent data suggest, that PIBF production is not exclusively a pregnancy-related phenomenon. PIBF is present in most undifferentiated tissues, e.g. malignant tumors. The possible role of PIBF in tumor development will be discussed.     

Progesterone directly and indirectly affects perforin expression in cytolytic cells

PROBLEM: Decidual lymphocytes (DL) expressing the cytolytic molecule perforin represent approximately 55% of DL in the first trimester of human pregnancy. Progesterone dominates this phase of pregnancy and controls the production of uterine cytokines and growth factors. The aim of this study was to investigate the role of progesterone and progesterone-induced blocking factor (PIBF) on perforin expression in DL and peripheral blood lymphocytes (PBL). METHOD OF STUDY: Perforin expression was analyzed in PBL and DL incubated either in culture medium or with decidual adherent cells (DAC) and peripheral blood adherent cells (PBAC) and their supernatants with or without progesterone or PIBF. Perforin was detected by flow cytometry in PB and in decidual first trimester pregnancy lymphocytes. RESULTS: Progesterone in high concentrations directly affects perforin expression in DL but not in PBL. Progesterone in a concentration dependent manner indirectly blocks perforin expression in DL and PBL cultured with adherent cells or their supernatants. PIBF blocked upregulation of perforin expression of DL cultured with DAC, but none of those cultured with PBAC. Similarly, PIBF was inefficient when PBL or DL were cultured with PBAC. CONCLUSION: Progesterone present in a high concentration locally at the maternal-fetal interface modulates perforin expression in the first trimester pregnancy DL.     

The Immunological Pregnancy Protective Effect of Progesterone Is Manifested via Controlling Cytokine Production

PROBLEM: This study was aimed at investigating the involvement of an altered cytokine pattern in the immunomodulatory and anti-abortive effects of a progesterone-induced immunomodulatory protein (PIBF). METHOD: PIBF expression on lymphocytes of healthy pregnant women and from women at risk for premature pregnancy termination was determined. In sera of the same women TNFα was quantified by a bioassay using L929 cells. NK activity was determined by a single cell cytotoxicity assay. Cytokine production of the lymphocytes or murine spleen cells was measured by ELISA or detected by immunocytochemistry. In pregnant mice endogenous PIBF activity was neutralized by anti-PIBF IgG. RESULTS: Sera of women at risk for premature pregnancy termination contained significantly higher concentrations of TNFα than those from healthy pregnant women and PIBF expression on the lymphocytes was inversely related to serum concentration of TNFα. Increased NK activity of lymphocytes after neutralization of endogenous PIBF activity is corrected by anti-IL2 treatment and PIBF inhibits IL12 expression on activated lymphocytes. PIBF increases IL-10 production by activated spleen cells. In pregnant mice, neutralization of endogenous PIBF activity by specific antibody results in increased resorption rate and reduced splenic IL-10 production. CONCLUSIONS: Our data allow the assumption that via blocking IL-12 production PIBF inhibits NK activation with a concomitant reduction of TNFα levels. Disturbances in this system might lead to the expression of the known synergistic effect of IL-12 and TNFα, resulting in a Th1 type cytokine dominance and pregnancy termination.     

Evidence that the Expression of Progesterone-Induced Blocking Factor by Maternal T-Lymphocytes Is Positively Correlated with Conception

PROBLEM: To compare the expression by T-lymphocytes of an immunomodulatory protein known as progesterone-induced blocking factor (PIBF) in conception versus non-conception cycles even when there has been definite fertilization and embryo formation. METHOD: PIBF expression on T lymphocytes was measured using an immunohistochemical method with a PIBF-specific polyclonal antibody. These levels were determined in patients undergoing three types of therapy: non-in vitro fertilization (IVF), IVF-embryo transfer (ET), and frozen ET. Sera were drawn 12 days from ovulation in non-IVF cycles or 9 days after ET and were assayed for PIBF and beta human chorionic gonadotropin. Comparison of the frequency of lymphocyte expression of PIBF in pregnant versus non-pregnant women were made. RESULTS: PIBF was detected in 29.5% of non-pregnant women and 52.5% of pregnant women. There were no differences in PIBF levels by therapy used in non-pregnant cases or in the pregnant group. CONCLUSION: These data are consistent with the hypothesis that maternal expression of PIBF in T-lymphocytes soon after trophoblast invasion may depend on successful implantation.     

PIBF: The Double Edged Sword. Pregnancy and Tumor

Citation Szekeres‐Bartho J, Polgar B. PIBF: The Double Edged Sword. Pregnancy and Tumor. Am J Reprod Immunol 2010; 64: 77–86 Problem The role of progesterone‐dependent immunomodulation in the maintenance of normal pregnancy. Methods In vitro and in vivo data on the effect that progesterone and its mediator progesterone‐induced blocking factor (PIBF) exert on the immune functions of pregnant women are reviewed, together with clinical findings. Results Activated pregnancy lymphocytes express progesterone receptors, which enable progesterone to induce a protein called PIBF. PIBF increases Th2 type cytokine production by signaling via a novel type of IL‐4 receptor and activating the Jak/STAT pathway. PIBF inhibits phosholipase A2, thus reduces prostaglandin synthesis. PIBF inhibits perforin release in human decidual lymphocytes and reduces the deleterious effect of high NK activity on murine pregnancy. PIBF production is a characteristic feature of normal human pregnancy, and its concentration is reduced in threatened pregnancies. PIBF mRNA and protein are expressed in a variety of malignant tumors. Inhibition of PIBF synthesis increases survival rates of leukemic mice. Conclusion Progesterone‐induced blocking factor is produced by pregnancy lymphocytes and also by malignant tumors. The PIBF‐induced Th2‐dominant immune response is favorable during pregnancy but might facilitate tumor growth by suppressing local antitumor immune responses.     

The Expression of a Progesterone-Induced Immunomodulatory Protein in Pregnancy Lymphocytes

PROBLEM : The immunological effects of progesterone are mediated by a protein, named the progesterone-induced blocking factor (PIBF). The PIBF blocks NK activity in vitro and therefore prevents the abortive effect of high NK activity in mice. Increased NK activity has been suggested to play a role in pregnancy termination; thus NK inhibitory effect of the PIBF should contribute to the maintenance of normal gestation. This study was designed to investigate the relationship between in vivo PIBF-producing capacity and in vitro cytotoxic activity of pregnancy lymphocytes, as well as the clinical status or the outcome of pregnancy. METHOD : Lymphocytes of 168 pregnant women (96 normal pregnancies, 16 showing clinical symptoms of threatened preterm pregnancy termination, 46 recurrent aborters, and 10 women sampled at the onset of spontaneous abortion or preterm delivery) were isolated on Ficoll-Paque gradient. The lymphocytes were tested for reactivity with a PIBF-specific antibody by immunocytochemistry, and simultaneously for cytotoxic activity to human embryonic fibroblast targets. RESULTS : The percentage of PIBF-positive lymphocytes in peripheral blood of healthy pregnant women was significantly higher than in that of women at risk for premature pregnancy termination. In peripheral blood of patients undergoing spontaneous pregnancy termination at the time of sampling, and in those of women showing symptoms of premature pregnancy termination we found lower than normal percentage of PIBF-positive cells. PIBF expression of the lymphocytes showed an inverse correlation with NK activity, and the rate of PIBF positive lymphocytes was related to the outcome of pregnancy. CONCLUSION : These data suggest a strong relationship between PIBF producing capacity as well as NK activity of the lymphocytes and the success of gestation.     

Progesterone induced blocking factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity

PROBLEM: Progesterone induced blocking factor (PIBF) is a mediator of progesterone that blocks peripheral blood lytic natural killer (NK) activity. Progesterone or PIBF stimulated decidual macrophages block up-regulation of perforin expression in decidual lymphocytes (DL). Therefore, we investigated whether progesterone regulates cytotoxicity of DL. METHOD OD STUDY: Decidual mononuclear cells were cultured with progesterone. PIBF, progesterone and anti-PIBF antibody or in the medium only. Cytolytic activity of non-adherent DL was measured by PKH-26 (red) 2 hr cytolytic assay and flow cytometry. Perforin positive DL were detected by immunofluorescency and PIBF-positive cells by immunohistology. RESULTS: Progesterone and PIBF, in a dose-dependent manner decreased cytotoxicity of DL against K-562 targets, and perforin egzocytosys was blocked. Anti-PIBF antibodies reversed the progesterone mediated reduction in cytolytic activity of DL. PIBF positive cells were found in first trimester pregnancy decidua. CONCLUSION: The results indicate possible role for PIBF, as a mediator of progesterone in regulation of DL cytolytic activity at the maternal-foetal (M-F) interface.     

Cytokine Production by Lymphocytes in Pregnancy

PROBLEM: In the presence of progesterone lymphocytes of pregnant women release a 34- kDa protein named the progesterone-induced blocking factor (PIBF). PIBF mediates the immunomodulatory and anti-abortive effects of progesterone and its presence is related to the outcome of pregnancy. PIBF induces production of Th2 type cytokines by activated lymphocytes. The in vivo relationship between PIBF- and cytokine production of pregnancy lymphocytes and the outcome of pregnancy was investigated. METHOD OF STUDY: Interleukin (IL)-12 and IL-10 production and PIBF expression in peripheral lymphocytes of 111 healthy pregnant women and 120 women at risk for premature pregnancy termination were detected by immunocytochemistry. RESULTS: We found increased IL-12 and low PIBF and IL-10 expression on lymphocytes of “risk” patients, and a high rate of IL-10 and PIBF positivity on lymphocytes from healthy pregnant women. The cytokine production pattern of the lymphocytes was related to the presence or absence of previous abortions as well as to the outcome of pregnancy. CONCLUSION: These data suggest the involvement of an altered cytokine production pattern in the immunologic effects of progesterone.     

Correlations of the expression of γδ T cells and their co‐stimulatory molecules TIGIT,PD‐1, ICOS and BTLA with PR and PIBF in the peripheral blood and decidual tissues of women with unexplained recurrent spontaneous abortion

Semi‐allogeneic embryos are not rejected by the maternal immune system due to maternal–fetal immune tolerance. Progesterone (P) receptor (PR)‐expressing γδ T cells are present in healthy pregnant women. In the presence of P, these cells secrete an immunomodulatory protein called progesterone‐induced blocking factor (PIBF), which can facilitate immune escape and is important in preventing embryonic rejection. This work investigated the correlations of the expression of γδ T cells and their co‐stimulatory molecules T cell immunoglobulin and ITIM domain (TIGIT), programmed cell death 1 (PD‐1), inducible co‐stimulator (ICOS) and B and T lymphocyte attenuator (BTLA) with progesterone receptor (PR) and progesterone‐induced blocking factor (PIBF) in peripheral blood and decidual tissue in women with unexplained recurrent spontaneous abortion (URSA) and normal pregnant (NP) women. We confirmed that γδ T cell proportions and PIBF expression in the peripheral blood and decidua of URSA women decreased significantly, while PR expression in decidua decreased. However, TIGIT, PD‐1, ICOS and BTLA expression in γδ T cells in peripheral blood did not change, while TIGIT and PD‐1 expression in γδ T cells in decidua increased significantly. Under the action of PHA‐P (10 µg/ml), co‐blocking of TIGIT (15 µg/ml) and PD‐1 (10 µg/ml) antibodies further induced γδ T cell proliferation, but PIBF levels in the culture medium supernatant did not change. At 10^?10 M P, γδ T cells proliferated significantly, and PIBF concentrations in the culture medium supernatant increased. γδ T cells co‐cultured with P, TIGIT and PD‐1 blocking antibodies showed the most significant proliferation, and PIBF concentrations in the culture medium supernatant were the highest. These results confirm that P is necessary for PIBF production. The TIGIT and PD‐1 pathways participate in γδ T cell proliferation and activation and PIBF expression and play important roles in maintaining pregnancy.     

Progesterone-induced blocking factor inhibits degranulation of natural killer cells.

PROBLEM: During the first trimester of pregnancy, nonclassical (CD3-, CD56+, CD16-, perforin [P]bright+) natural killer (NK) cells comprise the major decidual lymphocyte population. These cells, in spite of their high perforin content, exert a low cytolytic activity. Peripheral blood lymphocytes of healthy pregnant women produce progesterone-induced blocking factor (PIBF), which inhibits NK activity. PIBF-producing cells are likely to be present in decidua and might contribute to low decidual NK activity. METHOD OF STUDY: Decidual cells obtained from elective pregnancy termination were double labeled for CD56 and PIBF. We tested the effect of PIBF on perforin liberation by activated peripheral blood NK cells. RESULTS: Sixty percent of decidual lymphocytes were CD56 + and expressed PIBF at the same time. PIBF-treated and untreated peripheral blood NK cells were incubated with K-562 cells, and perforin content of target conjugated NK cells was detected with immunocytochemistry. PIBF treatment of peripheral blood lymphocytes significantly reduced lysis of K-562 cells. Among target bound lymphocytes in PIBF-treated samples, we found a significantly (P < 0.01) higher rate of P+ cells than in untreated samples. CONCLUSIONS: These data suggest that PIBF inhibits cytotoxicity of NK cells via a block of degranulation, and since decidual NK cells are PIBF+, it cannot be ruled out that this effect of PIBF contributes to low decidual NK activity.     

Progesterone regulates IL12 expression in pregnancy lymphocytes by inhibiting phospholipase A2

PROBLEM: Progesterone-induced blocking factor (PIBF) is one of the pathways that mediate the immunological effects of progesterone. PIBF inhibits natural killer (NK) cytotoxic activity. Recently we showed that neutralization of PIBF results in an increased interleukin (IL)-12 expression, which is corrected by cyclooxygenase inhibitors. As exogenous arachidonic acid (AA) voids the NK blocking effect of PIBF, it is likely that PIBF acts before the level of the cyclooxygenase enzyme. Therefore in this study we investigated the effect of PIBF neutralizing antibody and simultaneous phospholipase A2 inhibitor quinacrine (Q) treatment on IL-12 production. METHODS: Pregnancy lymphocytes were treated with anti-PIBF antibody or lipopolysaccharide (LPS) as a positive control, in the presence or absence of Q. IL-12 expression by PBMC was detected by immunocytochemistry. RESULTS: Neutralization of PIBF as well as LPS treatment resulted in an increased IL-12 expression, which was corrected by simultaneous Q treatment. Pre-treatment of lymphocytes with progesterone prevented the stimulating effect of LPS on IL-12 production. CONCLUSION: Progesterone binding of the lymphocytes is followed by the release of PIBF that inhibits AA release. The subsequent block of prostaglandin synthesis reduces IL-12 production and results in a lowered cytotoxic NK activity, which may contribute to a normal pregnancy outcome.     

孕激素诱导的封闭因子在先兆流产患者血清中的表达

目的通过检测先兆流产患者血清中孕酮及孕激素诱导的封闭因子（PIBF）的表达水平,探讨PIBF与先兆流产的关系及临床意义。方法先兆流产患者72例为观察组,同期健康早孕妇女40例为对照组,采用酶联免疫吸附方法（ELISA）检测血清中孕酮及PIBF水平并进行对比分析。结果两组孕妇的年龄、妊娠时间和血清孕酮水平比较差异无统计学意义（P〉0.05）;观察组PIBF水平为（103.91±25.12）ng/ml,明显低于对照组的（117.62±24.33）ng/ml,差异有统计学意义（P〈0.05）。观察组血清孕酮水平与PIBF之间不存在相关关系（P〉0.05）,对照组血清孕酮水平与PIBF之间存在相关关系（P〈0.05）。结论 PIBF表达降低与自然流产的发生有关系,妊娠早期血清PIBF水平降低是引起自然流产的原因之一。     

Progesterone and Non-specific Immunologic Mechanisms in Pregnancy

PROBLEM: Progesterone-dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone-induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti-abortive effect in mice. Recently we have shown that PIBF induces a Th2 shift in vitro. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss. METHOD OF STUDY: Balb-c mice on day 8.5 of pregnancy were injected intraperitoneally with 0.5 mg of rabbit anti-PIBF immunoglobulin G (IgG). Another group of mice was simultaneously treated with anti-NK monoclonal antibodies. Mice treated with the same amount of normal rabbit serum or untreated mice of similar gestational age were used as controls. The animals were sacrificed on day 10.5, and their uteri were inspected. The ratio of living and resorbed embryos was determined. NK activity as well as cytokine expression on the spleen cells were determined by immunocytochemistry and enzyme-linked immunoadsorbent assay (ELISA). RESULTS: Mitogen-activated spleen cells from anti-PIBF-treated mice produced significantly (P < 0.001) less IL-10 than those of pregnant control mice. A significantly higher percentage (P < 0.001) of spleen cells from anti-PIBF-treated mice expressed interferon-γ (IFNγ) as determined by immunocytochemistry, than those of untreated pregnant mice. There was a positive relationship between the percentage of IFNγ-positive spleen cells and resorption rates, and an inverse relationship between the latter and interleukin-10 (IL-10) production. All these effects were corrected by treatment with anti-NK antibodies. CONCLUSION: Our data suggest that PIBF contributes to the success of gestation via eytokine-mediated inhibition of NK activity.     

Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion,implantation failures after IVF/ET or normal pregnancy

PROBLEM: We aimed to investigate absolute counts of intracellular T helper 1 (Th1) and Th2 cytokine expressing T-cell subpopulations in women with three or more recurrent spontaneous abortions (RSA), multiple implantation failures after in-vitro fertilization and embryo transfer (IVF/ET) (three or more) or during normal pregnancy. METHOD OF STUDY: Absolute cell counts and percentages of CD3+, CD3+/CD4+, and CD3+/CD8+ T-cell populations expressing intracellular cytokines [interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4 and IL-10] was studied by four-color flow cytometry in 15 RSA and 13 implantation failure patients. Eighteen fertile non-pregnant and 47 normal pregnant women were also compared with regard to intracellular cytokine expression. RESULTS: Interleukin-10 producing CD3+/CD8+ T-cell counts were significantly lower in women with RSA (P < 0.05) and implantation failures (P < 0.05), and TNF-alpha producing CD3+/CD4+ T-cell counts were higher in women with RSA (P < 0.05) and implantation failures (P < 0.005) than those of non-pregnant fertile controls. During normal pregnancies, first trimester IL-4 expressing CD3+, CD3+/CD4+ T-cell counts (P < 0.05) and IFN-gamma expressing CD3+ T-cell counts (P < 0.05) were significantly higher than those of third trimester (P < 0.05). First trimester TNF-alpha expressing CD3+/CD8+ T-cell counts were significantly higher than those of second and third trimester women (P < 0.05). However, there are no differences in cytokine expression between non-pregnant and first trimester pregnant women. CONCLUSION: Absolute counts of IFN-gamma, IL-4, and TNF-alpha expressing T cells decrease with the progress of gestation (third trimester) during normal pregnancies. In women with implantation failures, absolute cell counts of TNF-alpha expressing CD3+/ 4- cells reflects the presence of dominant Th1 immune response. A significantly increased Th1 cytokine expression may be the underlying immune etiology for reproductive failures.     

Progesterone-Induced Blocking Factor and Cytokine Profile in Women with Threatened Pre-Term Delivery

Problem  The objective of this study was to compare serum concentrations of progesterone-induced blocking factor (PIBF), anti-inflammatory (IL-10), and pro-inflammatory (IL-6, TNFα, and IFNγ) cytokines of women with threatened pre-term delivery, with those of women with normal pregnancy and to evaluate the impact of PIBF on the outcome of pregnancy.
Method of study  A prospective study was conducted on a sample of 30 women with threatened pre-term delivery (study group) and 20 healthy pregnant women (control group) between the 24th and 37th gestational weeks. Serum PIBF, anti-inflammatory (IL-10), and pro-inflammatory (IL-6, TNFα, and IFNγ) cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA).
Results  Thirteen of 30 patients (43.3%) with symptoms of threatened pre-term delivery, and one of 20 patients (5%) in the control group delivered before the 37th week of gestation. Mean PIBF concentrations in serum samples of patients with threatened pre-term delivery were significantly lower than in those of healthy pregnant women (171.12 ± 162.06 ng/mL versus 272.85 ± 114.87 ng/mL; P  < 0.05). Women with symptoms of threatened pre-term delivery had significantly lower serum levels of IL-10, and higher levels of IL-6 as well as IFNγ compared with healthy controls.
Conclusion  Our results indicate that measuring PIBF and cytokine concentrations in serum during pregnancy is feasible and may be important for understanding immunological causes of pre-term delivery.     

Interleukin-2 receptor concentrations in pregnant women with a history of recurrent miscarriage.

BACKGROUND: The mechanism by which the maternal immune system tolerates the fetus during pregnancy is unclear. METHODS: This study measured interleukin-2 receptor (IL-2R) concentrations in the serum of non-pregnant women (Group 1); healthy first trimester pregnant women (Group 2); pregnant women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester (Group 3); and first trimester pregnant women with a history of recurrent miscarriage but whose pregnancies on this occasion went successfully to term (Group 4). An initial sample was obtained from all women in Groups 1, 2, 3 and 4. A further sample was obtained 4 weeks later from women in Groups 1, 2 and 4. RESULTS: The initial sample showed no significant difference in IL-2R concentrations between Groups 1 and 2. Concentrations were significantly higher in Groups 3 (667 +/- 244 U/ml; P < 0.003) and 4 (730 +/- 360 U/ml; P < 0.05) compared with healthy pregnant women (425 +/- 94). When the second sample was obtained concentrations in Group 4 were found to have fallen so that they no longer differed from Group 2. CONCLUSIONS: Our results confirm earlier findings that a successful pregnancy is associated with significantly lower concentrations of IL-2R.     

The role of gamma/delta T cells in progesterone-mediated immunomodulation during pregnancy: a review.

PROBLEM: To determine if pregnancy is recognized by the immune system and if inadequate recognition of fetal antigens might result in failed pregnancy. METHOD OF STUDY: Review of literature and current data. RESULTS: In the decidua gamma/delta TCR positive cells significantly increase in number. A subset of gamma/delta T cells reacts with nonpolymorphic Class I or Class I like molecules. Trophoblast recognition is mediated by the V gamma 1 subset which recognize a conserved mammalian sequence on the trophoblast. Almost all gamma/delta T cells in the decidua are activated and use the V delta 1 chain, whereas the majority of human peripheral gamma/delta lymphocytes expresses V gamma 9/V delta 2 TCR. Peripheral gamma/delta T cells of healthy pregnant women preferentially use V gamma V delta 1 chains, on the other hand, those of recurrent aborters use the V gamma 9V delta 2 combination. Signaling via the V gamma 1.4V delta 1 receptor induces a Th2 type response, whereas activation of the lymphocytes via the V gamma 9V delta 2 receptor results in increased IL-12 production and natural killer (NK) activity. In the presence of progesterone, activated lymphocytes synthesize the progesterone induced blocking factor (PIBF), which inhibits NK activity and exerts an anti abortive effect in vivo. Decidual CD56+ and gamma delta+ cells are to a high extent the same population. CONCLUSION: All decidual CD56+ cells express PIBF, thus it cannot be excluded that local production of this substance contributes to low decidual NK activity and thus to the success of the pregnancy.     

The role of gamma/delta T-cell receptor-positive cells in pregnancy: part II.

PROBLEM: We have previously demonstrated a significantly increased ratio of gamma/delta T-cell receptor (TCR)-positive progesterone receptor(PR)-positive cells in the peripheral blood of healthy pregnant women compared to that of recurrent aborters or non-pregnant individuals. Treatment of pregnancy lymphocytes with a pan anti-gamma/delta TCR antibody inhibits progesterone-induced blocking factor (PIBF) production, increases natural killer (NK) activity, and alters the cytokine profile. The present study was aimed at investigating the role of the different gamma/delta subpopulations in these phenomena. METHOD OF STUDY: Peripheral blood lymphocytes from healthy pregnant women were incubated with either anti-gamma1.4 and delta1, or anti-gamma9 and delta2 antibodies. The effect of these treatments on PR induction and interleukin (IL)-10 and IL-12 expression were tested by immunocytochemistry. NK activity of anti-gamma/delta treated lymphocytes was also determined. RESULTS: In peripheral blood of healthy pregnant women, the most frequently occurring chain combination was gamma1.4/delta1, whereas in recurrent aborters, the gamma9/delta2 combination was predominant. Treatment of normal pregnancy lymphocytes with a mixture of gamma1.4 and delta1 antibodies resulted in a significantly reduced NK activity and increased PR and IL-10 expression, whereas treatment with a mixture of gamma9 and delta2 antibodies significantly reduced IL-10 production and slightly increased IL-12 production and NK activity. These data suggest the presence of two functionally distinct subpopulations in the peripheral blood of pregnant women.