title: Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.
abstract: Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4(+) and CD8(+) T cells, with reductions not only in potentially deleterious IFN-γ and TNF-α production but also in IL-10 and IL-5. Conversely, production of IL-4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL-4. This was accompanied by reduced T-cell proliferation. Using fetal and viral antigen-specific CD8(+) T-cell clones, we confirmed that this as a direct, nonantigen-specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4(+) and CD8(+) T cells responded to progesterone in a dose-dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal-fetal interface. This characterization of how progesterone modulates T-cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss.
authors.affiliation: Centre for Women's and Children's Health, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lissauer
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Suzy A
authors.initials: SA
authors.lastname: Eldershaw
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Charlotte F
authors.initials: CF
authors.lastname: Inman
authors.affiliation: Centre for Women's and Children's Health, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Aravinthan
authors.initials: A
authors.lastname: Coomarasamy
authors.affiliation: School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Paul A H
authors.initials: PA
authors.lastname: Moss
authors.affiliation: Centre for Women's and Children's Health, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kilby
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D005333:Fetus / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D011247:Pregnancy / Q000097:blood / Q000276:immunology*; D011374:Progesterone / Q000097:blood / Q000276:immunology*
chemical_list: D016207:Cytokines; D011374:Progesterone
keywords: Human; IL-4; Maternal-fetal tolerance; Progesterone; T cell