title: Ecto-ATPase CD39 Inactivates Isoprenoid-Derived Vγ9Vδ2 T Cell Phosphoantigens.
abstract: In humans, Vγ9Vδ2 T cells respond to self and pathogen-associated, diphosphate-containing isoprenoids, also known as phosphoantigens (pAgs). However, activation and homeostasis of Vγ9Vδ2 T cells remain incompletely understood. Here, we show that pAgs induced expression of the ecto-ATPase CD39, which, however, not only hydrolyzed ATP but also abrogated the γδ T cell receptor (TCR) agonistic activity of self and microbial pAgs (C5 to C15). Only mevalonate-derived geranylgeranyl diphosphate (GGPP, C20) resisted CD39-mediated hydrolysis and acted as a regulator of CD39 expression and activity. GGPP enhanced macrophage differentiation in response to the tissue stress cytokine interleukin-15. In addition, GGPP-imprinted macrophage-like cells displayed increased capacity to produce IL-1β as well as the chemokine CCL2 and preferentially activated CD161-expressing CD4(+) T cells in an innate-like manner. Our studies reveal a previously unrecognized immunoregulatory function of CD39 and highlight a particular role of GGPP among pAgs.
authors.affiliation: Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol-Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Gruenbacher
authors.affiliation: Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol-Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gander
authors.affiliation: Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol-Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rahm
authors.affiliation: Department of Pulmonary Medicine, University Medical Center Freiburg, 79106 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.affiliation: Peter Gorer Department of Immunobiology, King's College London, London SE1 9RT, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nussbaumer
authors.affiliation: Immunotherapy Unit, Department of Urology, Medical University of Innsbruck and K1 Center Oncotyrol-Center for Personalized Cancer Medicine, 6020 Innsbruck, Austria. Electronic address: martin.thurnher@i-med.ac.at.
authors.forename: Martin
authors.initials: M
authors.lastname: Thurnher
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001081:Apyrase / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D004790:Enzyme Induction; D006801:Humans; D006868:Hydrolysis; D008213:Lymphocyte Activation; D018345:Mice, Knockout; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology; D013729:Terpenes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D001324:Autoantigens; D016692:Receptors, Antigen, T-Cell, gamma-delta; D013729:Terpenes; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D001081:Apyrase; C067869:CD39 antigen