title: Granulocytic myeloid-derived suppressor cells maintain feto-maternal tolerance by inducing Foxp3 expression in CD4+CD25-T cells by activation of the TGF-β/β-catenin pathway.
abstract: The transforming growth factor (TGF)-β/β-catenin pathway is involved in granulocytic myeloid-derived suppressor cell (G-MDSCs)-induced Foxp3 expression in CD4(+)CD25(-)T cells, which plays an essential role in maintaining feto-maternal tolerance.
  
  
  
  Decidual G-MDSCs play an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, which is dependent on TGF-β/β-catenin pathway.
  
  
  
  MDSCs contribute to the observed increase in regulatory T cells in animal cancer models. The TGF-β/β-catenin pathway is required for T cell development and survival.
  
  
  
  MDSC levels in deciduas from patients undergoing elective termination of pregnancy or spontaneous abortion were assessed by flow-cytometric analysis. The best characterized markers of G-MDSCs cells were examined by immunocytochemistry and flow-cytometric analysis. In vivo, fetus resorption and proportion of decidual immune cells were evaluated after depletion of G-MDSCs. In vitro, we established an antigen-non-specific (CD3/CD28) CD4(+)CD25(-)T and G-MDSC co-culture system and added TGF-β, anti-TGFβ, TGF-β plus anti-TGFβ or β-catenin inhibitor ICG001 to the system. Protein levels were measured by western blot.
  
  
  
  G-MDSCs showed a significant decrease in spontaneous abortion compared with elective abortion in women with normal pregnancy (P < 0.01), whereas the numbers of monocytic MDSCs remained unchanged. The dynamics of G-MDSCs in mice revealed that few G-MDSCs were present in non-pregnant uteri. G-MDSCs expanded rapidly in CBA/J×BALB/c mice with normal pregnancy and decreased in CBA/J×DBA/2 mice with abortion-prone pregnancy. G-MDSCs were characterized by the expression of CD115, CD117, CD135, CD62L, CCR2, MHCII, CD80, Arginase I and iNOS, and a lack of F4/80 or CD11c expression. Specifically, depletion of G-MDSCs-induced severe embryo resorption and decreased the percentage of CD4(+)CD25(+)Foxp3(+)T cells. In vitro, G-MDSCs had an important role in promoting Foxp3 induction in CD4(+)CD25(-)T cells, dependent on TGF-β/β-catenin pathway.
  
  
  
  It is not sufficient to examine the role of G-MDSCs in the maintenance of maternal-fetal tolerance by depleting G-MDSCs using neutralizing antibody. Further studies are needed to establish an animal model of G-MDSCs in order to elucidate their exact role at the maternal-fetal tolerance.
  
  
  
  Our findings provide novel insights into a new function and mechanism of action for G-MDSCs in mediating feto-maternal immune tolerance.
  
  
  
  Not applicable.
  
  
  
  This research was supported by the National Natural Science Foundation of China (Grant No. 81270715; 91442113). The authors have nothing to disclose.
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Kang
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Zhilan
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Tongfei
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai JiaoTong University, 1630 Dongfang Road, Shanghai 200127, P. R. China Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, P. R. China zamzkh0526@126.com.
authors.forename: Aimin
authors.initials: A
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D051176:beta Catenin
keywords: feto-maternal tolerance; forkhead box P3; myeloid-derived suppressor cells; transforming growth factor-β; β-catenin