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Abstract
Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses.
Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.
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1 University Medical Center Hamburg-Eppendorf, Department of Immunology, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
2 University Medical Center Schleswig-Holstein, Division of Pediatric Pneumology & Allergology, Lübeck, Germany (GRID:grid.412468.d) (ISNI:0000 0004 0646 2097); Airway Research Center North, Member of the German Center for Lung Research, Lübeck, Germany (GRID:grid.412468.d)
3 University Medical Center Hamburg-Eppendorf, Department of Cellular and Integrative Physiology, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
4 University Medical Center Hamburg-Eppendorf, Department of Neurosurgery, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
5 University Medical Center Hamburg-Eppendorf, Department of Biochemistry and Molecular Cell Biology, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
6 Core Facility Fluorescence Cytometry, Research Center Borstel, Borstel, Germany (GRID:grid.418187.3) (ISNI:0000 0004 0493 9170)
7 Technology Platform Microscopy and Image Analysis, Heinrich Pette Institute/Leibniz Institute for Experimental Virology, Hamburg, Germany (GRID:grid.418481.0) (ISNI:0000 0001 0665 103X)
8 University Medical Center Hamburg-Eppendorf, Department of Neurology, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
9 University of Lübeck, Department of Pediatrics and Adolescent Medicine, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672)
10 University Medical Center Hamburg-Eppendorf, I. Department of Medicine, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484); University Medical Center Hamburg-Eppendorf, Department of General, Visceral and Thoracic Surgery, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484)
11 University of Bonn, Department of Pharmaceutical & Medicinal Chemistry, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300)
12 University Medical Center Hamburg-Eppendorf, I. Department of Medicine, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484); University Medical Center Hamburg-Eppendorf, Department of General, Visceral and Thoracic Surgery, Hamburg, Germany (GRID:grid.13648.38) (ISNI:0000 0001 2180 3484); Karolinska Institute and University Hospital, Immunology and Allergy Unit, Department of Medicine, Solna, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626)