Immunomodulatory molecules are released from the first trimester and term placenta via exosomes

Abstract

The semiallogenic fetus is tolerated by the maternal immune system through control of innate and adaptive immune responses. Trophoblast cells secrete nanometer scale membranous particles called exosomes, which have been implicated in modulation of the local and systemic maternal immune system. Here we investigate the possibility that exosomes secreted from the first trimester and term placenta carry HLA-G and B7 family immunomodulators. Confocal microscopy of placental sections revealed intracellular colocalization of B7-H1 with CD63, suggesting that B7-H1 associates with subcellular vesicles that give rise to exosomes. First trimester and term placental explants were then cultured for 24 hours. B7H-1 (CD274), B7-H3 (CD276) and HLA-G5 were abundant in pelleted supernatants of these cultures that contained microparticles and exosomes; the latter, however, was observed only in first trimester pellets and was nearly undetectable in term explant-derived pellets. Further purification of exosomes by sucrose density fractionation confirmed the association of these proteins specifically with exosomes. Finally, culture of purified trophoblast cells in the presence or absence of EGF suggested that despite the absence of HLA-G5 association with term explant-derived exosomes, it is present in exosomes secreted from mononuclear cytotrophoblast cells. Further, differentiation of cytotrophoblast cells reduced the presence of HLA-G5 in secreted exosomes. Together, the results suggest that the immunomodulatory proteins HLA-G5, B7-H1 and B7-H3, are secreted from early and term placenta, and have important implications in the mechanisms by which trophoblast immunomodulators modify the maternal immunological environment.

Placenta-derived exosomes: potential biomarkers of preeclampsia

“…92 However, a more recent study showed that B7 immunomodulatory molecules and HLAG5 are secreted via exosomes from early and term placentas. 93 This study offered a novel perspective in which human placenta-derived exosomes may have served directly as key mediators of maternal immunotolerance to the semiallogeneic fetus. The identification of these key immunoregulatory proteins bound to placenta-derived exosomes supports the fact that exosomes have an immunomodulatory role in preventing the degradation of invading trophoblastic cells by inducing maternal T-cell apoptosis, which could play a key role in maternal complications, such as PE, fetal rejection, and intrauterine growth restriction.…”

HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism

“…In agreement with this, in myeloma cells mHLA-G is also released from the cell membrane in microparticles. 35 These findings suggest that quantification of sHLA-G may be clinically useful and more informative than analysis of the surface of tumor cells.…”

NF-kB Regulation in T-cells in Pregnancy is Mediated via Fas/FasL Interactions: The Signal for which is Derived from Exosomes Present in Maternal Plasma

“…Indeed despite Vacchio and Hodes [31] demonstrating that fetal FasL expression induced CD8 + T-cell tolerance to the fetal antigen H-Y during pregnancy, and that the loss of placental FasL is associated with increased fetal loss and thus small litter sizes [32], Chaouat and Clark suggested that apoptosis of T-cells in allopregnancies were mediated via mechanisms other than Fas + /FasL + [33]. Those alternate mechanisms would no doubt include TRAIL/TRAIL receptors (DR4 and DR5) and PD-L1/PD-1, another immune modulating moiety known to be expressed on exosomes [34].…”