title: The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy.
abstract: Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3(+) dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3(+) but not Tim-3(-) dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Medical Center for Human Reproduction, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Zhou
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Song-Cun
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Maternal and Child Care Hospital of Huangpu District, Shanghai, China.
authors.forename: Yun-Lan
authors.initials: YL
authors.lastname: Jiang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Hai-Lan
authors.initials: HL
authors.lastname: Piao
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China.
authors.forename: Mei-Rong
authors.initials: MR
authors.lastname: Du
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018920:Coculture Techniques; D003656:Decidua / Q000276:immunology / Q000473:pathology; D005260:Female; D037161:Galectins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008431:Maternal-Fetal Exchange / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D054353:Perforin / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D061251:Primary Cell Culture; D015398:Signal Transduction; D014327:Trophoblasts / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C508598:IL4 protein, human; C105032:LGALS9 protein, human; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D015847:Interleukin-4