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.
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.
Zenclussen
Ana Claudia
AC
Institut für Medizinische Immunologie, Biomedizinisches Forschungszentrum, Raum 2.0534, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, D-13353, Berlin, Germany. ana.zenclussen@charite.de
Gerlof
Katrin
K
Zenclussen
Maria Laura
ML
Sollwedel
André
A
Bertoja
Annarosa Zambon
AZ
Ritter
Thomas
T
Kotsch
Katja
K
Leber
Joachim
J
Volk
Hans-Dieter
HD
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
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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