title: 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.
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.
authors.affiliation: Institut für Medizinische Immunologie, Biomedizinisches Forschungszentrum, Raum 2.0534, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353, Berlin, Germany. ana.zenclussen@charite.de
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
authors.forename: Katrin
authors.initials: K
authors.lastname: Gerlof
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Zenclussen
authors.forename: André
authors.initials: A
authors.lastname: Sollwedel
authors.forename: Annarosa Zambon
authors.initials: AZ
authors.lastname: Bertoja
authors.forename: Thomas
authors.initials: T
authors.lastname: Ritter
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
authors.forename: Joachim
authors.initials: J
authors.lastname: Leber
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis*; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005220:Fathers; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011247:Pregnancy; D011270:Pregnancy, Animal; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015704:CD4 Antigens; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; D016753:Interleukin-10
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