Murine T Cell Determination of Pregnancy Outcome: I. Effects of Strain, αβ T Cell Receptor, γδ T Cell Receptor, and γδ T Cell Subsets

Authors

  • Petra C. Arck,

    1. Departments of Medicine, Pathology, Obstetrics and Gynaecology, Molecular Virology-Immunology Program, McMaster University Hamilton, Ontario, Canada
    2. Amgen Institute, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
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  • David A. Ferrick,

    1. Amgen Institute, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
    2. University of California at Davis, Department of Microbiology and Pathology, Davis, California, USA
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  • Darlene Steele-Norwood,

    1. Departments of Medicine, Pathology, Obstetrics and Gynaecology, Molecular Virology-Immunology Program, McMaster University Hamilton, Ontario, Canada
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  • Ken Croitoru,

    1. Departments of Medicine, Pathology, Obstetrics and Gynaecology, Molecular Virology-Immunology Program, McMaster University Hamilton, Ontario, Canada
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  • David A. Clark

    Professor, Corresponding author
    1. Departments of Medicine, Pathology, Obstetrics and Gynaecology, Molecular Virology-Immunology Program, McMaster University Hamilton, Ontario, Canada
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Rm. 3V39, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.

Abstract

PROBLEM: T cells bearing αβ T cell receptor (TcR) and γδ TcR are present at the fetomaternal interface, and the latter, which express surface activation markers, can react with fetal trophoblast cell antigens. What is the role of these cells?

METHOD: Using stress-abortion-prone DBA/2-mated CBA/J and abortion-resistant C57/B16 mice, αβ, γδ, and CD8+/- T cell subsets were measured in spleen and uterine decidua. The effect of immunization against abortion and administration of anti-TcR antibody in vivo was examined. Cytokine synthesis was measured by intracellular staining of Brefeldin A-treated cells.

RESULTS: Abortion-prone matings showed an unexpected accumulation of γδ T cells beginning in the peri-implantation period and this was suppressed by immunization against abortion. The immunization deleted γδ T cells producing the abortogenic cytokines, TNF-α and γ-interferon, and increased production of the anti-abortive cytokines, IL-10 and transforming growth factor-β2 (TGF-β2). Immunization also boosted the number of αβ T cells which were present in the decidua as early as 2 days after implantation. In vivo injection of GL4 (anti-δ) depleted γδ T cells producing Th1 cytokines in the peri-implantation period, and prevented abortions, whereas H57 (anti-β) decreased the number of αβ T cells and led to 100% abortions. CD8+ T cells present in peri-implant decidua before onset of abortions were mostly αβ TcR+, although some were γδ+. Changes in γδ and αβ T cells in pregnancy were most dramatic in uterine tissue.

CONCLUSION: Although decidual γδ T cells after formation of a distinct placenta and fetus produce anti-abortive TGF-β2-like molecules and IL-10, prior events can lead to abortion. High local production of TNF-α and γ-interferon develop during the peri-implantation phase because of an excessive increase in the Th1 cytokine+ subset of γδ cells; these cytokines may be contributed by other tissues in decidua, and the contribution of bioactive factors by γδ T cells may augment the cytokine pool. In contrast, αβ T cells (which may be inactivated by stress that causes abortions) may mediate the anti-abortive effect of alloimmunization. Alloimmunization involves a shift from a Th1 to a Th2 pattern in the γδ T cells in decidua.

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