title: Mesenchymal stromal cells up-regulate CD39 and increase adenosine production to suppress activated T-lymphocytes.
abstract: Mesenchymal stromal cells (MSCs) suppress T cell responses through mechanisms not completely understood. Adenosine is a strong immunosuppressant that acts mainly through its receptor A(2a) (ADORA2A). Extracellular adenosine levels are a net result of its production (mediated by CD39 and CD73), and of its conversion into inosine by Adenosine Deaminase (ADA). Here we investigated the involvement of ADO in the immunomodulation promoted by MSCs. Human T lymphocytes were activated and cultured with or without MSCs. Compared to lymphocytes cultured without MSCs, co-cultured lymphocytes were suppressed and expressed higher levels of ADORA2A and lower levels of ADA. In co-cultures, the percentage of MSCs expressing CD39, and of T lymphocytes expressing CD73, increased significantly and adenosine levels were higher. Incubation of MSCs with media conditioned by activated T lymphocytes induced the production of adenosine to levels similar to those observed in co-cultures, indicating that adenosine production was mainly derived from MSCs. Finally, blocking ADORA2A signaling raised lymphocyte proliferation significantly. Our results suggest that some of the immunomodulatory properties of MSCs may, in part, be mediated through the modulation of components related to adenosine signaling. These findings may open new avenues for the development of new treatments for GVHD and other inflammatory diseases.
authors.affiliation: National Institute of Science and Technology in Stem Cell and Cell Therapy, Center for Cell Therapy, Regional Blood Center and Faculty of Medicine of Ribeirão Preto-University of São Paulo, Ribeirão Preto, Brazil. felipearaujo@usp.br
authors.forename: Felipe
authors.initials: F
authors.lastname: Saldanha-Araujo
authors.forename: Flávia I S
authors.initials: FI
authors.lastname: Ferreira
authors.forename: Patrícia V
authors.initials: PV
authors.lastname: Palma
authors.forename: Amélia G
authors.initials: AG
authors.lastname: Araujo
authors.forename: Regina H C
authors.initials: RH
authors.lastname: Queiroz
authors.forename: Dimas T
authors.initials: DT
authors.lastname: Covas
authors.forename: Marco A
authors.initials: MA
authors.lastname: Zago
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Panepucci
mesh_terms: D000241:Adenosine / Q000096:biosynthesis* / Q000276:immunology; D000243:Adenosine Deaminase / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis* / Q000276:immunology; D001081:Apyrase / Q000096:biosynthesis* / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D043705:Receptor, Adenosine A2A / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D043705:Receptor, Adenosine A2A; D000243:Adenosine Deaminase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine