Human placental trophoblast cells contribute to maternal–fetal tolerance through expressing IL-35 and mediating iTR35 conversion

• Published in: Nature communications Vol. 10; no. 1; pp. 1 - 10
• Main Authors: Liu, Jia, Hao, Shengnan, Chen, Xi, Zhao, Hui, Du, Lutao, Ren, Hanxiao, Wang, Chuanxin, Mao, Haiting
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/21; 13/31; 13/51; 14/1; 631/250/127/1213; 631/250/1619/554/1898/1271; 631/250/2152/569/2495; 631/250/516; 64/60; Cell proliferation; Chemokines; Cytokines; Fetuses; Genotype & phenotype; Humanities and Social Sciences; Immunological tolerance; Immunology; In vivo methods and tests; Interleukins; Lymphocytes; Lymphocytes T; Miscarriage; multidisciplinary; Phosphorylation; Placenta; Pregnancy; Proteins; Science; Science (multidisciplinary); Stat1 protein; Stat3 protein; Transcription factors; Trophoblasts; Womens health
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12484-z

During pregnancy, trophoblast cells sustain the maternal–fetal tolerance via expressing and secreting various chemokines and cytokines. Our previous study revealed the expression of interleukin-35 (IL-35) in human first-trimester trophoblasts. Here we show that IL-35 is expressed in both human first-trimester primary trophoblast cells and a trophoblast cell line. Trophoblast cells inhibit the proliferation of human naive conventional T cells (T conv cells) and convert suppressed T conv cells into iT R 35 in an IL-35-dependent manner. Mechanistically, trophoblast cell derived IL-35 mediates its function through phosphorylation of STAT1 and STAT3. In vivo studies confirm that mice with immunologically spontaneous abortion have lower levels of IL-35 and iT R 35 cells at the maternal–fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates. Meanwhile, exogenous IL-35 induces iT R 35 and prevents immunological abortion. Our findings thus suggest that trophoblast cells have a critical function in preserving maternal–fetal tolerance via secreting IL-35 during pregnancy. Trophoblasts play a critical role in maintaining immunological tolerance at maternal–fetal interface. Here the authors show that IL-35 is made by trophoblasts, converts T cells to immune tolerant iTR35 cells, and is critical to prevent spontaneous abortion.