Abnormal T-Cell Reactivity against Paternal Antigens in Spontaneous Abortion

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.

Maternal Acceptance of the Fetus: True Human Tolerance

“…In the mouse, it has recently been reported that CD4 ϩ CD25 ϩ Tregs expand during pregnancy and are required to prevent immunological rejection of the fetus (14). In another study, Zenclussen et al (15) demonstrated rescue of allogeneic pregnancy upon transfer of Tregs from normal pregnant mice to abortionprone mice. The data in humans are consistent with a similar function for Tregs in mouse pregnancy.…”

Immunological Analogy Between Allograft Rejection, Recurrent Abortion and Pre-Eclampsia – the Same Basic Mechanism?

“…Suppressor T CD8ϩ lymphocytes possessing progesterone receptor and secreting IL-10 and progesterone-induced blocking factor (PIBF) were shown to be another population of regulatory cells [136]. Compared to abortion-prone mice, normal pregnant mice also had elevated numbers of intrathymic CD4ϩC25ϩ as well as IL-10ϩ Treg cells, that could inhibit both proliferation and IFN␥ secretion of effector cells [137]. The depletion of Treg cells provoked pregnancy failure [138].…”

“…The depletion of Treg cells provoked pregnancy failure [138]. Transfer of CD4ϩCD25ϩ Treg cells was shown to prevent abortion but exclusively in that situation, when Treg cells originated from normal pregnant mice, suggesting that only Treg cells exposed previously to paternal antigens could exert regulatory activity in vivo [137]. Murine decidual CD4ϩCD25ϩ Treg cells could cooperate with dendritic cells (DCs).…”

Endometriosis-induced changes in regulatory T cells — insights towards developing permanent contraception

“…Development of Tregs in the thymus and periphery is dependent on expression of the transcription factor, forkhead box P3 (FoxP3), [31–33] and Foxp3 mRNA expression is decreased two-fold in women with primary infertility compared to fertile patients. Likewise, adoptive transfer of Tregs into abortion-prone CBA/J mice alleviates fetal rejection in the mice [34, 35]. Thus, dysregulated Treg activity may contribute to pregnancy loss and/or infertility.…”