A pivotal role for galectin-1 in fetomaternal tolerance

Abstract

A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

“…Experiments comparing syngeneic and allogeneic matings [CBA/Caj (H2 k ), C3H/j (H2 k ), and Balb/cJ (H2 d ) males] failed to show differences in the litter size or embryo resorption rates of pregnant C57BL/6 (H2 b ) gal1 Ϫ/Ϫ females (data not shown). However, it was reported recently that gal1 Ϫ/Ϫ 129P3/J females (H2 b ) mated with allogeneic DBA/J2 males (H2 d ) present greater fetal resorption rates than wild-type 129P3/J females, whereas no differences were observed in syngeneic matings (38), thus supporting an important role for gal1 in maternal-fetal immune tolerance. The fact that augmented embryo resorption rates in gal1 Ϫ/Ϫ pregnant females are evident only in matings with certain strain combinations is indicative of the presence of redundant systems to prevent fetal rejection.…”

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…Maternal stress is known to impair fetal development (13)(14)(15)(16). Early during gestation, exposing mouse dams to a sound stress challenge is associated with an increase in the fetal loss rate (25,46). To develop a mouse model of fetal-growth restriction and placental insufficiency, we exposed pregnant dams to sound stress at midgestation (gestation day [gd12.5]), when placentation is largely completed.…”

“…It has been proposed that progesterone, via the progesterone receptor and glucocorticoid receptor-dependent pathways (70), modulates the immune response during pregnancy, including CD4 + and CD8 + T cell differentiation (25,46,71). Interestingly, compared with WT mice, CD4 + T cells from Pgr -/-mice express lower levels of TGF-β1 (35) and produce significantly more IFN-γ upon stimulation (36).…”

“…When pregnancy commences, progesterone stimulates decidualization of endometrial stromal cells and maternal immune adaptation to pregnancy; it subsequently sustains uterine quiescence throughout pregnancy (23)(24)(25). There is a significant rise of progesterone during pregnancy, and even subtle deficits can affect the course of pregnancy by increasing the risk of miscarriage (26) or reduced birth weight (27,28).…”

HLA-G homodimer-induced cytokine secretion through HLA-G receptors on human decidual macrophages and natural killer cells

“…Protein secretion was also confirmed in the case of galectin-1. The secreted galectin-1 is involved in T cell apoptosis at the maternal-fetal interface in early human pregnancy (34) and appears to play an important role in maternalfetal tolerance (35). Other secreted proteins may also have important functions in maternal-fetal tolerance or another aspect of maternal-fetal physiology.…”