Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B Cells

Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed

Vesiclepedia: A compendium for extracellular vesicles with continuous community annotation

Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field

Immunosuppressive Protein Signatures Carried by Syncytiotrophoblast-Derived Exosomes and Their Role in Human Pregnancy

The syncytiotrophoblast (STB) of human placenta constitutively and throughout pregnancy produces and secretes exosomes - nanometer-sized membrane-bound extracellular vesicles from the endosomal compartment that convey cell-cell contact ‘by proxy’ transporting information between donor and recipient cells locally and at a distance. Released in the maternal blood, STB-derived exosomes build an exosomal gradient around the feto-placental unit acting as a shield that protects the fetus from maternal immune attack. They carry signal molecules and ligands that comprise distinct immunosuppressive protein signatures which interfere with maternal immune mechanisms, potentially dangerous for the ongoing pregnancy. We discuss three immunosuppressive signatures carried by STB exosomes and their role in three important immune mechanisms 1) NKG2D receptor–mediated cytotoxicity, 2) apoptosis of activated immune cells and 3) PD-1-mediated immunosuppression and priming of T regulatory cells. A schematic presentation is given on how these immunosuppressive protein signatures, delivered by STB exosomes, modulate the maternal immune system and contribute to the development of maternal-fetal tolerance

Immunosuppressive Protein Signatures Carried by Syncytiotrophoblast-Derived Exosomes and Their Role in Human Pregnancy

The syncytiotrophoblast (STB) of human placenta constitutively and throughout pregnancy produces and secretes exosomes - nanometer-sized membrane-bound extracellular vesicles from the endosomal compartment that convey cell-cell contact ‘by proxy’ transporting information between donor and recipient cells locally and at a distance. Released in the maternal blood, STB-derived exosomes build an exosomal gradient around the feto-placental unit acting as a shield that protects the fetus from maternal immune attack. They carry signal molecules and ligands that comprise distinct immunosuppressive protein signatures which interfere with maternal immune mechanisms, potentially dangerous for the ongoing pregnancy. We discuss three immunosuppressive signatures carried by STB exosomes and their role in three important immune mechanisms 1) NKG2D receptor–mediated cytotoxicity, 2) apoptosis of activated immune cells and 3) PD-1-mediated immunosuppression and priming of T regulatory cells. A schematic presentation is given on how these immunosuppressive protein signatures, delivered by STB exosomes, modulate the maternal immune system and contribute to the development of maternal-fetal tolerance