title: Interleukin-17-producing decidual CD4+ T cells are not deleterious for human pregnancy when they also produce interleukin-4.
abstract: BACKGROUND
  Trophoblast expressing paternal HLA-C antigens resemble a semiallograft, and could be rejected by maternal CD4+ T lymphocytes. We examined the possible role in human pregnancy of Th17 cells, known to be involved in allograft rejection and reported for this reason to be responsible for miscarriages. We also studied Th17/Th1 and Th17/Th2 cells never investigated before. We defined for the first time the role of different Th17 subpopulations at the embryo implantation site and the role of HLA-G5, produced by the trophoblast/embryo, on Th17 cell differentiation.
  
  
  METHODS
  Cytokine production by CD4+ purified T cell and T clones from decidua of normal pregnancy, unexplained recurrent abortion, and ectopic pregnancy at both embryo implantation site and distant from that site were analyzed for protein and mRNA production. Antigen-specific T cell lines were derived in the presence and in the absence of HLA-G5.
  
  
  RESULTS
  We found an associated spontaneous production of IL-17A, IL-17F and IL-4 along with expression of CD161, CCR8 and CCR4 (Th2- and Th17-type markers) in fresh decidua CD4+ T cells during successful pregnancy. There was a prevalence of Th17/Th2 cells (producing IL-17A, IL-17F, IL-22 and IL-4) in the decidua of successful pregnancy, but the exclusive presence of Th17 (producing IL-17A, IL-17F, IL-22) and Th17/Th1 (producing IL-17A, IL-17F, IL-22 and IFN-γ) cells was found in the decidua of unexplained recurrent abortion. More importantly, we observed that Th17/Th2 cells were exclusively present at the embryo implantation site during tubal ectopic pregnancy, and that IL-4, GATA-3, IL-17A, ROR-C mRNA levels increased in tubal biopsies taken from embryo implantation sites, whereas Th17, Th17/Th1 and Th1 cells are exclusively present apart from implantation sites. Moreover, soluble HLA-G5 mediates the development of Th17/Th2 cells by increasing IL-4, IL-17A and IL-17F protein and mRNA production of CD4+ T helper cells.
  
  
  CONCLUSIONS
  No pathogenic role of decidual Th17 cells during pregnancy was observed. Indeed, a beneficial role for these cells was observed when they also produced IL-4. HLA-G5 could be the key feature of the uterine microenvironment responsible for the development of Th17/Th2 cells, which seem to be crucial for successful embryo implantation.
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Lombardelli
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Logiodice
authors.affiliation: INSERM UMR1043, CNRS UMR5282, Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse III, 31024 Toulouse, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Aguerre-Girr
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Ornela
authors.initials: O
authors.lastname: Kullolli
authors.affiliation: Department of Gynecology and Obstetrics, Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia.
authors.forename: Herman
authors.initials: H
authors.lastname: Haller
authors.affiliation: INSERM UMR1043, CNRS UMR5282, Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse III, 31024 Toulouse, France.
authors.forename: Ysabel
authors.initials: Y
authors.lastname: Casart
authors.affiliation: Gynécologie-Obstétrique, Hôpital Paule de Viguier, Toulouse, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Berrebi
authors.affiliation: INSERM UMR1043, CNRS UMR5282, Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse III, 31024 Toulouse, France.
authors.forename: Fatima-Ezzahra
authors.initials: FE
authors.lastname: L'Faqihi-Olive
authors.affiliation: INSERM UMR1043, CNRS UMR5282, Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse III, 31024 Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Duplan
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Romagnani
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.affiliation: Department of Physiology and Immunology, Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rukavina
authors.affiliation: INSERM UMR1043, CNRS UMR5282, Centre de Physiopathologie Toulouse-Purpan, Université de Toulouse III, 31024 Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Bouteiller
authors.affiliation: Department of Experimental and Clinical Medicine and DENOTHE Excellence Center, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Piccinni
keywords: Ectopic pregnancy; IL-17; IL-4; Pregnancy; Spontaneous abortion; Th17