Li-Ping Jin

Human First-Trimester Trophoblast Cells Recruit CD56brightCD16− NK Cells into Decidua by Way of Expressing and Secreting of CXCL12/Stromal Cell-Derived Factor 1

More than 70% of decidual lymphocytes are NK cells characterized by CD56brightCD16− phenotype, but the mechanisms by which these NK cells are recruited in the decidua are still almost unrevealed. In this study, we first analyzed the transcription of 18 chemokine receptors in the first-trimester decidual CD56brightCD16− NK cells. Among these receptors, CXCR4 and CXCR3 were found highly transcribed, and the expression of CXCR4 was verified in most of the decidual CD56brightCD16− NK cells by flow cytometry. The first-trimester human trophoblasts were found expressing CXCL12/stromal cell-derived factor 1, the specific ligand of CXCR4, by way of in situ hybridization and immunohistochemistry. The primary cultured trophoblast cells were also found to secrete stromal cell-derived factor 1α spontaneously, and its concentration was 384.6 ± 90.7 pg/ml after the trophoblast cells had been cultured for 60 h. All of the ligands for CXCR3 were below the minimal detectable concentration when trophoblast cells were cultured for up to 48 h. Both recombinant human SDF-1α and supernatants of the cultured trophoblast cells exhibited chemotactic activity on decidual CD56brightCD16− NK cells. Our findings suggest that human first-trimester trophoblast cells produce CXCL12, which in turn chemoattracts decidual CD56brightCD16− NK cells. This activity could contribute to the recruitment mechanism of decidual lymphocytes, especially CD56brightCD16− NK cells, in decidua, and may be used at a local level to modulate the immune milieu at the materno-fetal interface.

Blockade of CD86 Signaling Facilitates a Th2 Bias at the Maternal-Fetal Interface and Expands Peripheral CD4+CD25+ Regulatory T Cells to Rescue Abortion-Prone Fetuses

Abstract Intervention in B7 (CD80/CD86)/B7-ligand (CD28/CTLA-4) pathways is an effective way of preventing unwanted immune responses, such as allograft rejection. Pregnancy maintenance represents maternal tolerance to the fetal allograft, which is accompanied by a type 2 helper cell (Th2) bias at the maternal-fetal interface. Here, the costimulatory signal of CD86 was selectively blocked, and that of CD80 was kept unimpaired by administration of anti-murine CD86 monoclonal antibody at the early gestational stage in abortion-prone CBA/J×DBA/2 matings and normal pregnant CBA/J×BALB/c matings. It was demonstrated that in vivo blockade of CD86 costimulation could suppress maternal immune attack to the fetus by shifting cytokines from Th1 predominance to Th2 bias at the maternal-fetal interface, and expanding peripheral CD4+CD25+ regulatory T cells, which play an important role in the development and maintenance of maternal-fetal tolerance. Furthermore, the expression of CD28 and its ligands CD80/CD86 on peripheral lymphocytes was down-regulated, whereas that of CTLA-4 was up-regulated, which might facilitate the suppressive effect of CD4+CD25+ regulatory T cells on the alloreactive T cells. The maternal-fetal immunotolerance induced by CD86 blockade decreased fetal resorption in CBA/J×DBA/2 matings, but did not affect normal pregnant CBA/J×BALB/c matings. These results suggest that selective blockade of CD86 costimulation leads to maternal immune tolerance to embryo antigen, and might contribute to a rational immunoregulatory regimen for recurrent spontaneous abortion.

Adoptive transfer of paternal antigen-hyporesponsive T cells facilitates a Th2 bias in peripheral lymphocytes and at materno-fetal interface in murine abortion-prone matings.

Problem  To investigate the Th1/Th2 cytokine changes in abortion‐prone recipient mice adoptively transferred by the paternal antigen‐hyporesponsive T cells.

Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-κB signaling in human early pregnancy.

Decidual stromal cells (DSCs) are an important component of decidual tissues where they are in strict proximity with immune cells. Although previous research has indicated that DSCs participate in the regulation of immune cells during pregnancy, the crosstalk between DSCs and decidual NK cells (dNKs) has not been fully elucidated. The aim of this study was to ascertain the effect of DSC-derived IL-33 on dNK function and explore the underlying mechanism. Flow cytometry showed a considerable increase in ST2 expression on dNKs compared with peripheral NKs (pNKs). Subsequent research found that perforin production, granzyme A production, and the cytolytic activity of dNKs were impaired by DSC media. Furthermore, the addition of DSC media induced an increase in Th2 cytokine production (IL-4, IL-13, and IL-10) with a concomitant decrease in Th1 cytokine expression (TNF-α) of dNKs. However, IFN-γ, another member of the Th1 cytokine family that is thought to be necessary during early gestation increased after IL-33 stimulation. DSC media sharply inhibited the expression of major activating receptors (NKp30, NKG2D) while up-regulating the levels of inhibitory receptor (KIR2DL1) on dNKs. The biological effect of DSC media on dNKs was abrogated by the administration of sST2. Moreover, Western blot analysis suggested that the NF-κB pathway was involved in the IL-33-induced changes in the phenotype and function of dNKs, which was further confirmed by pharmacological inhibition with the NF-κB inhibitor BAY 11-7082. Our results suggest that the crosstalk between DSCs and dNKs might play a crucial role in maintaining successful pregnancy.

Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1/2 and PI3K signaling pathways in human early pregnancy

Chemokine CCL24, acting through receptor CCR3, is a potent chemoattractant for eosinophil in allergic diseases and parasitic infections. We recently reported that CCL24 and CCR3 are co-expressed by trophoblasts in human early pregnant uterus. Here we prove with evidence that steroid hormones estradiol (E), progesterone (P), and human chorionic gonadotropin (hCG), as well as decidual stromal cells (DSCs) could regulate the expression of CCL24 and CCR3 of trophoblasts. We further investigate how trophoblast-derived CCL24 mediates the function of trophoblasts in vitro, and conclude that CCL24/CCR3 promotes the proliferation, viability and invasiveness of trophoblasts. In addition, analysis of the downstream signaling pathways of CCL24/CCR3 show that extracellular signal-regulated kinases (ERK1/2) and phosphoinositide 3-kinase (PI3K) pathways may contribute to the proliferation, viability and invasiveness of trophoblasts by activating intracellular molecules Ki67 and matrix metallopeptidase 9 (MMP9). However, we did not observe any inhibitory effect on trophoblasts when blocking c-Jun N-terminal kinase (JNK) or p38 pathways. In conclusion, our data suggests that trophoblast-derived CCL24 at the maternal-fetal interface promotes trophoblasts cell growth and invasiveness by ERK1/2 and PI3K pathways. Meanwhile, pregnancy-related hormones (P and hCG), as well as DSCs could up-regulate CCL24/CCR3 expression in trophoblasts, which may indirectly influence the biological functions of trophoblasts. Thus, our results provide a possible explanation for the growth and invasion of trophoblasts in human embryo implantation.