title: Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface.
abstract: OBJECTIVE
  Are the immune regulatory molecules programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) involved in regulating CD4+ T cell function during pregnancy?
  
  
  CONCLUSIONS
  PD-1 and Tim-3 promote Type 2 helper T cell (Th2) bias and pregnancy maintenance by regulating CD4+ T cell function at the maternal-fetal interface.
  
  
  BACKGROUND
  The maternal CD4+ T cell response to fetal antigens is thought to be an important component of maternal-fetal tolerance during pregnancy. PD-1 and Tim-3 are important for limiting immunopathology. The co-expression of PD-1 and Tim-3 on T cells identifies a T cell subset with impaired proliferation and cytokine production. Combined blockade of Tim-3 and PD-1 could restore T cell function to the greatest degree.
  
  
  METHODS
  The expression of PD-1 and Tim-3 on CD4+ T cells was analyzed by flow cytometry, and in vitro and in vivo analyses were used to investigate the role of PD-1/Tim-3 signal in the regulation of CD4+ T cells function and pregnancy outcome.
  A total of 88 normal pregnant women, 37 women with recurrent spontaneous abortion, 36 normal pregnant mice and 45 abortion-prone mice were included. We measure the expression of PD-1 and Tim-3 on CD4+ T cells and their relationship to the function of CD4+ T cells and pregnancy outcome, as well as the effects of blocking PD-1 and Tim-3 pathways on decidual CD4+ T (dCD4+ T) cells during early pregnancy.
  
  
  RESULTS
  PD-1 and Tim-3, by virtue of their up-regulation on dCD4+ T cells during pregnancy, define a specific effector/memory subset of CD4+ T cells and promote Th2 bias at the maternal-fetal interface. Using in vitro and in vivo experiments, we also found that combined targeting of PD-1 and Tim-3 pathways results in decreased production of Th2-type cytokines by dCD4+ T cells and increased fetal resorption of normal pregnant murine models. Moreover, decreased PD-1 and Tim-3 on dCD4+ T cells may be associated with miscarriage.
  Further study is required to examine the mechanism of PD-1 and Tim-3 effects on Th2 cytokine production by CD4+ T cells during pregnancy.
  
  
  CONCLUSIONS
  These results have important implications for understanding the physiological mechanisms that promote maternal-fetal tolerance. Our study also indicates that targeting Tim-3 and PD-1 pathways may represent novel therapeutic strategies to prevent pregnancy loss.
  
  
  BACKGROUND
  This study was supported by the National Basic Research Program of China (2015CB943300); National Nature Science Foundation of China (81490744, 91542116, 31570920, 81070537, 31171437, 81370770, 31270969, 31570920, 91542116); the Key Project of Shanghai Municipal Education Commission (14ZZ013) and the Key Project of Shanghai Basic Research from Shanghai Municipal Science and Technology Commission (12JC1401600). None of the authors have any conflict of interest to declare.
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: SongCun
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: XiaoYong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: YuanYuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, 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 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: YanHong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, 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 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: HaiLan
authors.initials: H
authors.lastname: Piao
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China mrdu@fudan.edu.cn djli@shmu.edu.cn.
authors.forename: DaJin
authors.initials: D
authors.lastname: Li
authors.affiliation: Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China mrdu@fudan.edu.cn djli@shmu.edu.cn.
authors.forename: MeiRong
authors.initials: M
authors.lastname: Du
mesh_terms: D000026:Abortion, Habitual / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000028:Abortion, Induced; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003433:Crosses, Genetic; D003656:Decidua / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005327:Fetal Resorption / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D051379:Mice; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015149:Tocolytic Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D057134:Antibodies, Neutralizing; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D015149:Tocolytic Agents
keywords: CD4+T; PD-1; Th2 bias; Tim-3; miscarriage; pregnancy; trophoblast