title: 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 co-localization 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 h. 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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Kshirsagar
authors.forename: S M
authors.initials: SM
authors.lastname: Alam
authors.forename: S
authors.initials: S
authors.lastname: Jasti
authors.forename: H
authors.initials: H
authors.lastname: Hodes
authors.forename: T
authors.initials: T
authors.lastname: Nauser
authors.forename: M
authors.initials: M
authors.lastname: Gilliam
authors.forename: C
authors.initials: C
authors.lastname: Billstrand
authors.forename: J S
authors.initials: JS
authors.lastname: Hunt
authors.forename: M G
authors.initials: MG
authors.lastname: Petroff
mesh_terms: D060887:B7 Antigens / Q000378:metabolism*; D060890:B7-H1 Antigen / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D055252:Cell-Derived Microparticles / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D059951:HLA-G Antigens / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D020033:Protein Isoforms / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D060887:B7 Antigens; D060890:B7-H1 Antigen; D015415:Biomarkers; D059951:HLA-G Antigens; D007155:Immunologic Factors; D051907:Lysosomal Membrane Proteins; D020033:Protein Isoforms; D060149:Tetraspanin 30; C423236:CD274 protein, human; C423237:CD276 protein, human; C554586:CD63 protein, human; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1