title: Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy.
abstract: OBJECTIVE
  To investigate whether pregnancy-induced regulatory T cells are generated specifically for paternal antigens or expanded by hormonal changes and to study regulatory T cell-related mechanisms during pregnancy.
  
  
  METHODS
  We used murine models of normal, abortion-prone, and pseudopregnancy to characterize regulatory T cells and hormones by methods such as flow cytometry, molecular biology techniques, and chemiluminescence. Antigen specificity was studied in experiments in which animals were vaccinated with paternal antigens or adoptively transferred with regulatory T cells. To analyze regulatory T cell-mediated mechanisms, we used neutralizing antibodies against IL-10 or TGF-beta.
  
  
  RESULTS
  Regulatory T cells are activated by male antigens, and minor antigens are protected by linked immunosuppression. Our data exclude the possibility that regulatory T cell expansion during pregnancy is exclusively driven by hormonal changes. An increase in systemic regulatory T cell levels in pseudopregnant females after mating with vasectomized males but not after pseudopregnancy induced mechanically confirms generation of regulatory T cells specific for paternal antigens. As for the mechanisms, neutralizing IL-10 abrogates the protective effect of regulatory T cells, whereas blockage of TGF-beta does not provide the same effect.
  
  
  CONCLUSIONS
  Our data confirm that regulatory T cells act in an antigen-specific manner during pregnancy and strongly suggest that IL-10 is involved in regulatory T cell-mediated protection of the fetus. These data contribute to the knowledge of the basic mechanisms regulating immune tolerance during pregnancy, a major biologic question with important medical implications.
  
  
  METHODS
  II.
authors.affiliation: Institute of Medical Immunology, Charité, Universitätsmedizin, Berlin, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.forename: Paul O
authors.initials: PO
authors.lastname: Wafula
authors.forename: Annarosa Zambon
authors.initials: AZ
authors.lastname: Bertoja
authors.forename: André
authors.initials: A
authors.lastname: Sollwedel
authors.forename: Catharina
authors.initials: C
authors.lastname: Thuere
authors.forename: Ivonne
authors.initials: I
authors.lastname: Wollenberg
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*; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D004195:Disease Models, Animal; D005220:Fathers; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000276:immunology* / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology* / Q000637:transplantation; D016212:Transforming Growth Factor beta
chemical_list: D016212:Transforming Growth Factor beta; D016753:Interleukin-10