Tim-3 regulates the immunosuppressive function of decidual MDSCs via the Fyn-STAT3-C/EBPβ pathway during Toxoplasma gondii infection

• Published in: PLoS pathogens Vol. 19; no. 4; p. e1011329
• Main Authors: Qi, Houbao, Li, Yuantao, Liu, Xianbing, Jiang, Yuzhu, Li, Zhidan, Xu, Xiaoyan, Zhang, Haixia, Hu, Xuemei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2023; Public Library of Science (PLoS)
• Subjects: Animals; Biology and Life Sciences; Cell growth; Cell proliferation; Cytokines; Decidua; Female; Fetuses; Flow cytometry; Fyn protein; Galectin-9; Hepatitis A Virus Cellular Receptor 2 - genetics; Hepatitis A Virus Cellular Receptor 2 - metabolism; Humans; Immune checkpoint; Immunological tolerance; Infections; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - metabolism; Kinases; Ligands; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Microbalances; Monocytes; Myeloid-Derived Suppressor Cells - metabolism; Phosphorylation; Pregnancy; Pregnancy Outcome; Proteins; Research and Analysis Methods; Signal transduction; Spleen; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Statistical analysis; Suppressor cells; Toxoplasma - metabolism; Toxoplasma gondii; Toxoplasmosis - metabolism
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011329

Myeloid-derived suppressor cells (MDSCs) play a key role in maintaining maternal-fetal tolerance for a successful pregnancy, but the role of MDSCs in abnormal pregnancy caused by Toxoplasma gondii infection is unknown. Herein, we revealed a distinct mechanism by which T-cell immunoglobulin domain and mucin domain containing protein-3 (Tim-3), an immune checkpoint receptor that balances maternal-fetal tolerance during pregnancy, contributes to the immunosuppressive function of MDSCs during T. gondii infection. The expression of Tim-3 in decidual MDSCs was significantly downregulated following T. gondii infection. The proportion of monocytic MDSCs population, the inhibitory effect of MDSCs on T-cell proliferation, the levels of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs were all decreased in T. gondii-infected pregnant Tim-3 gene knockout (Tim-3KO) mice compared with infected pregnant WT mice. After treatment with Tim-3-neutralizing Ab in vitro, the expression levels of Arg-1, IL-10, C/EBPβ, and p-STAT3 were decreased, the interaction between Fyn and Tim-3 or between Fyn and STAT3 was weakened, and the binding ability of C/EBPβ to the promoters of ARG1 and IL10 was decreased in human decidual MDSCs with T. gondii infection, while opposite results were observed following treatment with galectin-9 (a ligand for Tim-3). Inhibitors of Fyn and STAT3 also downregulated the expression of Arg-1 and IL-10 in decidual MDSCs and exacerbated adverse pregnancy outcomes caused by T. gondii infection in mice. Therefore, our studies discovered that the decrease of Tim-3 after T. gondii infection could downregulate the functional molecules of Arg-1 and IL-10 expression in decidual MDSCs through the Fyn-STAT3-C/EBPβ signaling pathway and weaken their immunosuppressive function, which eventually contribute to the development of adverse pregnancy outcomes.