CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression
Enja Schneider, Riekje Winzer, Anne Rissiek, Isabell Ricklefs, Catherine Meyer‐Schwesinger, Franz Ricklefs, Andreas Bauche, Jochen Behrends, Rudolph Reimer, Santra Brenna, Hauke Wasielewski, Melchior Lauten, Björn Rissiek, Berta Puig, Filippo Cortesi, Tim Magnus, Ralf Fliegert, Christa E. Müller, Nicola Gagliani, Eva Tolosa
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.