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Extracellular and intracellular adenine nucleotides (AN) impact on all central processes in biology and medicine. AN are essential and ubiquitous signaling molecules involved in regulating universal cellular processes, including (i) cell-cell communication and (ii) intracellular signaling.
Unresolved issues regarding the signaling function of extracellular AN in inflammation, e.g. adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD), relate to the timing and location of their release, their conversion by ecto-enzymes, and their biological role within the balance of inflammatory processes. Likewise, the precise role of intracellular AN second messengers, e.g. nicotinic acid adenine dinucleotide phosphate (NAADP) or 3’,5’-cyclic adenosine monophosphate (cAMP), in the spatio-temporal control of signaling processes by forming or modulating microdomains with their metabolizing enzymes, specific binding proteins or receptors, or target ion channels remains largely unknown.
The central goal of the research consortium is to further our understanding of the regulatory roles of AN and their kinetics in the context of inflammatory diseases. Specific aims relate to (i) modulation of the balance between pro- and anti-inflammatory processes by AN converting ecto-nucleotidases and purinergic receptors, and to (ii) AN-driven intracellular calcium signaling and cAMP signaling in inflammation.
PAPER SCIENCE SIGNALING
Early steps in T cell activation are mediated by the synthesis of Ca2+-mobilizing second messenger NAADP. In this publication NAADPH-oxidizing enzymes that were critical for the early phases of T cell activation were identified. In cultured rat T cells, knockout of DUOX2 reduced local Ca2+ microdomain formation, whereas functional knockout of both DUOX1 and DUOX2 in murine T cells suppressed global intracellular Ca2+ signaling. This work was part of project A01 and A02 in close collaboration with projects A03, A04 and A10.
PAPER NATURE COMMUNICATIONS
Adenosine is a potent anti-inflammatory molecule generated by the ectonucleotidase CD73. In this publication Enja Schneider, Riekje Winzer et al. show that activated human CD8 T cells release CD73-containing extracellular vesicles which produce adenosine. This T cell-intrinsic mechanism of immune suppression contests the common paradigm that regulatory T cells must provide the whole machinery for adenosine production. This work was part of the A14 project (Tolosa/Gagliani) in close collaboration with projects A01, A05, A11 and A13
For further announcements see:
Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C. LC, Winterberg k, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks BP, Guse AH (2021) Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation. Sci. Signal. 14, eabe3800.
Schneider E, Winzer R, Rissiek A, Ricklefs I, Meyer-Schwesinger C, Ricklefs FL, Bauche A, Behrends J, Reimer R, Brenna S, Wasielewski H, Lauten M, Rissiek B, Puig B, Cortesi F, Magnus T, Fliegert R, Müller CE, Gagliani N, Tolosa E (2021) CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression. Nat Commun 12, 5911.
Kurelic R, Krieg PF, Sonner JK, Bhaiyan G, Ramos GC, Frantz S, Friese MA, Nikolaev VO (2021) Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk. Front. Pharmacol. 12:748798.
Leutert M, Duan Y, Winzer R, Menzel S, Tolosa E, Magnus T, Hottinger MO, Koch-Nolte F, Rissiek B (2021) Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation. Front. Immunol. 12:703719
Woelk LM, Kannabiran SA, Brock VJ, Gee CE, Lohr C, Guse AH, Diercks BP, Werner R (2021) Time-Dependent Image Restoration of Low-SNR Live-Cell Ca2 Fluorescence Microscopy Data. Int J Mol Sci. 22:11792.
Yang S*, Constantin OM*, Sachidanandan D*, Hofmann H, Kunz TC, Kozjak-Pavlovic V, Oertner TG, Nagel G, Kittel RJ, Gee CE*, Gao S* (2021) PACmn for improved optogenetic control of intracellular cAMP. BMC Biol. 19:227.
Conte G, Menéndez-Méndez A, Bauer S, El-Naggar H, Alves M, Nicke A, Delanty N, Rosenow F, Henshall DC, Engel T (2021) Circulating P2X7 Receptor Signaling Components as Diagnostic Biomarkers for Temporal Lobe Epilepsy. Cells. 10:2444.
Baum N, Eggers M, Koenigsdorf J, Menzel S, Hambach J, Staehler T, Fliegert R, Kulow F, Adam G, Haag F, Bannas P, Koch-Nolte F (2021) Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells. Front Immunol. 12:703574.
Brauneck F*, Weimer P*, Schulze zur Wiesch J, Weisel K, Leypoldt L, Vohwinkel G, Fritzsche B, Bokemeyer C, Wellbrock J, Fiedler W (2021) Bone Marrow-Resident Vδ1 T Cells Co-express TIGIT With PD-1, TIM-3 or CD39 in AML and Myeloma. Front. Med. 8:763773
Müller CE, Namasivayam V. Recommended tool compounds and drugs for blocking P2X and P2Y receptors. Purinergic Signal. 2021 online ahead of print