title: Tim-3 Is Upregulated in NK Cells during Early Pregnancy and Inhibits NK Cytotoxicity toward Trophoblast in Galectin-9 Dependent Pathway.
abstract: NK cells accumulate at the maternal-fetal interface (MFI) and play essential roles in maintaining immune tolerance during pregnancy. The mechanisms that facilitate NK cells tolerance to fetal tissue are largely unknown. T cell Ig and mucin domain-containing protein 3 (Tim-3) is a newly defined molecule with essential immunological function in many physiological and pathological processes. Recent study showed that Tim-3 was involved in the regulation of immune tolerance at MFI. However, whether Tim-3 regulates NK cells cytotoxicity toward trophoblasts is unclear. Here, we showed Tim-3 was mainly expressed by decidual NK cells (dNK) and Tim-3 level in dNK was higher than peripheral NK cells (pNK). Tim-3(+) dNK expressed more levels of mature markers CD94 and CD69 than Tim-3- dNK cells and blocking Tim-3 significantly inhibited dNK IFN-γ and TNF-α secretion. Furthermore, we found TGF-β1 may contribute to such up-regulation of Tim-3 in NK cells. Interestingly, blocking Tim-3 enhanced NK cytotoxicity toward trophoblast cell line HTR-8 but not K562. We found HTR-8 expressed Tim-3 ligand Galectin-9, in contrast K562 did not. Small interfering RNA-mediated silencing of Galectin-9 expression enhanced NK cytotoxicity toward HTR-8. We further showed Tim-3/Galecin-9 inhibited NK cytotoxicity toward trophoblast partially via impairing the degranulation process. In addition, clinical data showed that abnormal Tim-3 level on pNK might be associated with recurrent spontaneous abortion (RSA). Thus, our data demonstrate Tim-3/Galectin-9 pathway maintains local tolerance by suppressing NK cytotoxicity toward trophoblasts which may represent a new immunologic tolerance mechanism at MFI.
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Jintang
authors.initials: J
authors.lastname: Sun
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Meixiang
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Ban
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Gao
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Song
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Shao
authors.affiliation: Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Beihua
authors.initials: B
authors.lastname: Kong
authors.affiliation: Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xun
authors.initials: X
authors.lastname: Qu
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D003656:Decidua / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D037161:Galectins / Q000235:genetics / Q000378:metabolism*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007124:Immunoenzyme Techniques; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1