title: Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells.
abstract: The maternal immune system needs to adapt to tolerate the semi-allogeneic conceptus. Since maternal allo-reactive lymphocytes are not fully depleted, other local/systemic mechanisms play a key role in altering the immune response. The Th1/Th2 cytokine balance is not essential for a pregnancy to be normal. The immune cells, CD4+CD25+Foxp3+, also known as regulatory T cells (Tregs), step in to regulate the allo-reactive Th1 cells. In this review we discuss the role of Tregs in foeto-maternal immune tolerance and in recurrent miscarriage as well as their potential use as a new target for infertility treatment. Animal and human experiments showed Treg cell number and/or function to be diminished in miscarriages. Murine miscarriage can be prevented by transferring Tregs from normal pregnant mice. Tregs at the maternal-fetal interface prevented fetal allo-rejection by creating a "tolerant" microenvironment characterised by the expression of IL-10, TGF-β and haem oxygenase isoform 1 (HO-1) rather than by lowering Th1 cytokines. Tregs increase placental HO-1. In turn, HO-1 may lead to up-regulation of TGF-β, IL-10 and CTLA-4. In vivo experiments showed Tregs sensitisation from paternal antigens to be essential for maternal-fetal tolerance. Tregs increase throughout pregnancy and diminish in late puerperium. Recent data also support the capacity of Tregs to block maternal effector T cells, thereby reducing the maternal-fetal pathological responses to paternal antigens. These findings also permit us to consider new strategies for improving pregnancy outcomes, i.e., anti-TNF blockers and granulocyte-colony stimulating factors as well as novel approaches to therapeutically exploiting Treg + cell memory.
authors.affiliation: Systemic Autoimmune Disease Unit, Department of Internal Medicine I, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain; Department of Medicine, Faculty of Medicine, Universitat Autonoma, Barcelona, Spain. Electronic address: 16297jar@comb.es.
authors.forename: J
authors.initials: J
authors.lastname: Alijotas-Reig
authors.affiliation: High Obstetric Risk Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Llurba
authors.affiliation: Reproductive Medicine Unit, Obstetric Department, Vall d'Hebron University Hospital, Universitat Autonoma, Barcelona, Spain.
authors.forename: J Ma
authors.initials: JM
authors.lastname: Gris
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology; D000818:Animals; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007247:Infertility, Female / Q000276:immunology; D011247:Pregnancy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
keywords: Cytokines; Maternal–fetal tolerance; Miscarriages; NK cells/KIR; Regulatory-T lymphocytes; Treatment