RESUMO
Mechanisms accounting for the protection of the fetal semi-allograft from maternal immune cells remain incompletely understood. In previous studies, we showed that galectin-1 (Gal1), an immunoregulatory glycan-binding protein, hierarchically triggers a cascade of tolerogenic events at the mouse fetomaternal interface. Here, we show that Gal1 confers immune privilege to human trophoblast cells through the modulation of a number of regulatory mechanisms. Gal1 was mainly expressed in invasive extravillous trophoblast cells of human first trimester and term placenta in direct contact with maternal tissue. Expression of Gal1 by the human trophoblast cell line JEG-3 was primarily controlled by progesterone and pro-inflammatory cytokines and impaired T-cell responses by limiting T cell viability, suppressing the secretion of Th1-type cytokines and favoring the expansion of CD4(+)CD25(+)FoxP3(+) regulatory T (T(reg)) cells. Targeted inhibition of Gal1 expression through antibody (Ab)-mediated blockade, addition of the specific disaccharide lactose or retroviral-mediated siRNA strategies prevented these immunoregulatory effects. Consistent with a homeostatic role of endogenous Gal1, patients with recurrent pregnancy loss showed considerably lower levels of circulating Gal1 and had higher frequency of anti-Gal1 auto-Abs in their sera compared with fertile women. Thus, endogenous Gal1 confers immune privilege to human trophoblast cells by triggering a broad tolerogenic program with potential implications in threatened pregnancies.
Assuntos
Aborto Habitual/imunologia , Galectina 1/imunologia , Trofoblastos/imunologia , Linhagem Celular , Sobrevivência Celular/imunologia , Citocinas/imunologia , Galectina 1/antagonistas & inibidores , Galectina 1/biossíntese , Humanos , Progesterona/farmacologia , Linfócitos T/citologia , Linfócitos T/imunologia , Trofoblastos/citologiaRESUMO
We investigated the immunomodulatory role of chemokines in the maternal allogeneic T-cell response. In comparison with fertile women, we found in patients with recurrent spontaneous abortions (RSA), a significant decreased sera level of RANTES that increased after immunization with paternal leukocytes. Since blocking factors with unknown identity are detected in sera from fertile women, we hypothesized that RANTES might function as a novel blocking factor and therefore we explored its cell growth inhibitory properties during the allogenic T-cell response. We demonstrated that RANTES inhibits the mixed lymphocyte reaction (MLR) in a dose-dependent manner. Investigation of the mechanisms involved in cell growth inhibition revealed that this beta-chemokine induces T-cell apoptosis through modulation of Bcl-2 protein levels and by a caspase-independent mechanism and does not involve modulation of Fas (CD95) antigen expression. Our results provides experimental evidence implicating RANTES as a suppressor of alloantigen specific T-cell responses and indicates that this beta-chemokine might function as a novel blocking factor and reliable marker for successful allotreatment of RSA patients.