Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model.

Institut für Medizinische Immunologie, Biomedizinisches Forschungszentrum, Raum 2.0534, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353, Berlin, Germany.
American Journal Of Pathology (Impact Factor: 4.6). 03/2005; 166(3):811-22.
Source: PubMed

ABSTRACT Mammalian pregnancy is thought to be a state of immunological tolerance. The mechanisms underlying this phenomenon are still poorly understood. Here, we determined whether an inappropriate function of T regulatory (Treg) cells is involved in the pathogenesis of spontaneous abortion. We evaluated spleen and decidual lymphocytes from CBA/J mice undergoing immunological abortion (DBA/2J-mated) or having normal pregnancy (BALB/c-mated) on day 14 of gestation for ex vivo cytokine production after PMA or paternal antigen (alloantigen) stimulation. Treg activity was characterized by quantifying CD4(+)CD25(+) cells, foxp3 expression, and interleukin-10 secretion. Decidual lymphocytes from abortion CBA/J mice contained a significantly higher frequency of interferon-gamma-producing T cells specific for paternal antigens compared to those from normal pregnancy (7.8% versus 2.7%, P < 0.05). Compared to virgin CBA/J females, normal pregnant mice showed strongly elevated numbers of CD4(+)CD25(+) and interleukin-10(+) Treg cells in the thymus whereas significantly lower frequencies of Treg cells were observed in abortion mice. Very interestingly, CD4(+)CD25(+) Treg cells from normal pregnant and nonpregnant CBA/J mice could inhibit both proliferation and interferon-gamma secretion of lymphocytes from abortion mice in vitro whereas in vivo prevention of fetal rejection could only be achieved after adoptive transfer of Treg cells from normal pregnant mice. Our data suggest that pregnancy-induced Treg cells play a vital role in maternal tolerance to the allogeneic fetus.

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    ABSTRACT: Pregnancy establishment and maintenance represents a challenge for the maternal immune system because it has to be alert against pathogens while tolerating paternal alloantigens expressed in fetal structures. Regulatory T cells (Tregs) are important for successful implantation and involved in allotolerance towards paternal antigens. The origin and mechanisms leading to Treg generation during pregnancy at different stages remain under discussion. We report an accumulation of Helios(+) Tregs in thymus and in the lymph nodes draining the uterus at early pregnancy. At later pregnancy stages an expanded population of Foxp3(+) Tregs was generated in the periphery as we showed in a Rag-1(-/-) model of cell transfer. Our data suggest that Tregs, predominantly of thymic origin, are needed for pregnancy establishment. At later pregnancy stages an extra thymic Treg population contributes to the Treg pool in the periphery. Our data provides new insights in the origin of Tregs during pregnancy that are essential to understand natural mechanisms of tolerance acquisition.
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