title: Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β.
abstract: Levels of anti-inflammatory extracellular adenosine are controlled by the sequential action of the ectonucleotidases CD39 and CD73, whose expression in CD4(+)  T cells has been associated with natural regulatory T cells (nTregs). We here show that CD73 expression on activated murine CD4(+)  T cells is induced by TGF-β independently of Foxp3 expression, operates at the transcriptional level and translates into gain of functional capacity to generate adenosine. In the presence of AMP, CD73 induced by TGF-β generates adenosine able to suppress proliferation of activated CD4(+)  T cells in vitro. These effects are contextual and opposed by proinflammatory cytokines. CD73 is also upregulated by TGF-β in CD8(+)  T cells, DCs and macrophages, so providing an amplification mechanism for adenosine generation in tissue microenvironments. Together, these findings expose a novel anti-inflammatory role for TGF-β.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, UK.
authors.forename: Frederico S
authors.initials: FS
authors.lastname: Regateiro
authors.forename: Duncan
authors.initials: D
authors.lastname: Howie
authors.forename: Kathleen F
authors.initials: KF
authors.lastname: Nolan
authors.forename: Eleftherios I
authors.initials: EI
authors.lastname: Agorogiannis
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D015720:5'-Nucleotidase / Q000096:biosynthesis / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000378:metabolism; D000954:Antigens, Surface; D001081:Apyrase / Q000096:biosynthesis / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000737:chemistry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D018836:Inflammation Mediators; D007962:Leukocytes / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D016212:Transforming Growth Factor beta; D000249:Adenosine Monophosphate; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine