title: PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model.
abstract: OBJECTIVE
  Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect paternal/fetal antigens from rejection by maternal effector cells. Accordingly, the transfer of Treg obtained from BALB/c-mated CBA/J females prevents abortion in DBA/2J-mated animals. The actual mechanism through which Treg mediate their protective effect is still inconclusive. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and Programmed cell death 1 (PD-1) are some of known Treg-associated molecules; however, their role in Treg-mediated fetal protection in murine model has not been investigated.
  
  
  METHODS
  Treg obtained from normal pregnant animals (NP; CBA/J x BALB/c) on day 14 were adoptively transferred into abortion-prone mice (AP; CBA/J x DBA/2J) intravenously on day 2 of pregnancy. An amount of 250 microg of either anti-PD-1 or anti-CTLA-4 mAb were injected intraperitoneally on days 0, 3, 6 and 9 of pregnancy. Controls received Treg + IgG or Treg + PBS. NP or AP treated with PBS served as additional controls.
  
  
  RESULTS
  Blocking PD-1 abrogated the protective effect of Treg, resulting in a higher median abortion rate in comparison with the Treg/isotype-treated control while CTLA-4 blockage did not interfere with the protective effect of Treg. This was associated with a diminished number of vascular endothelial growth factor-A(+) cells, previously reported as stimulators of lymphocyte extravasation in preterm labor.
  
  
  CONCLUSIONS
  Our data suggest PD-1 as an important mediator in Treg-induced fetal protection in the CBA/J x DBA/2J murine model.
authors.affiliation: Institute of Medical Immunology, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Paul Ojiambo
authors.initials: PO
authors.lastname: Wafula
authors.forename: Ana
authors.initials: A
authors.lastname: Teles
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.forename: Kerstin
authors.initials: K
authors.lastname: Pohl
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D004195:Disease Models, Animal; D018450:Disease Progression; D004198:Disease Susceptibility; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011247:Pregnancy; D061026:Programmed Cell Death 1 Receptor; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D042461:Vascular Endothelial Growth Factor A