title: Adenosinergic Immunosuppression by Human Mesenchymal Stromal Cells Requires Co-Operation with T cells.
abstract: Mesenchymal stem/stromal cells (MSCs) have the capacity to counteract excessive inflammatory responses. MSCs possess a range of immunomodulatory mechanisms, which can be deployed in response to signals in a particular environment and in concert with other immune cells. One immunosuppressive mechanism, not so well-known in MSCs, is mediated via adenosinergic pathway by ectonucleotidases CD73 and CD39. In this study, we demonstrate that adenosine is actively produced from adenosine 5'-monophosphate (AMP) by CD73 on MSCs and MSC-derived extracellular vesicles (EVs). Our results indicate that although MSCs express CD39 at low level and it colocalizes with CD73 in bulge areas of membranes, the most efficient adenosine production from adenosine 5'-triphosphate (ATP) requires co-operation of MSCs and activated T cells. Highly CD39 expressing activated T cells produce AMP from ATP and MSCs produce adenosine from AMP via CD73 activity. Furthermore, adenosinergic signaling plays a role in suppression of T cell proliferation in vitro. In conclusion, this study shows that adenosinergic signaling is an important immunoregulatory mechanism of MSCs, especially in situations where ATP is present in the extracellular environment, like in tissue injury. An efficient production of immunosuppressive adenosine is dependent on the concerted action of CD39-positive immune cells with CD73-positive cells such as MSCs or their EVs.
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Erja
authors.initials: E
authors.lastname: Kerkelä
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Anita
authors.initials: A
authors.lastname: Laitinen
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Räbinä
authors.affiliation: Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Valkonen
authors.affiliation: Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Takatalo
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Larjo
authors.affiliation: Institute of Clinical Medicine, Division of Surgery.|Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.|Clinical Research Center, Department of Surgery and Intensive Care, Oulu University Hospital, Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Veijola
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Milla
authors.initials: M
authors.lastname: Lampinen
authors.affiliation: Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Siljander
authors.affiliation: Institute of Clinical Medicine, Division of Surgery.|Institute of Biomedicine, Department of Anatomy and Cell Biology, University of Oulu, Oulu, Finland.|Clinical Research Center, Department of Surgery and Intensive Care, Oulu University Hospital, Oulu, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Kaija
authors.initials: K
authors.lastname: Alfthan
authors.affiliation: Finnish Red Cross Blood Service, Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Laitinen
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics; D000241:Adenosine / Q000096:biosynthesis; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001081:Apyrase / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000235:genetics*; D000067128:Extracellular Vesicles / Q000276:immunology; D058851:GPI-Linked Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D058851:GPI-Linked Proteins; D000249:Adenosine Monophosphate; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine
keywords: Adenosine; CD73; Immunosuppression; Mesenchymal stromal cells; T cells