CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression

Enja Schneider,Björn Rissiek,Christa E Müller,Riekje Winzer,Melchior Lauten,Santra Brenna,Berta Puig,Nicola Gagliani,Anne Rissiek,Jochen Behrends,Isabell Ricklefs,Franz Ricklefs ,Ralf Fliegert,Catherine Meyer-Schwesinger,Hauke Wasielewski,Rudolph Reimer,Andreas Bauche,Tim Magnus,Filippo Cortesi,Eva Tolosa

doi:10.1038/s41467-021-26134-w

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.

Highlights

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation
In human peripheral blood (PB) T cells, CD73 is predominantly expressed on CD8 T cells (Fig. 1f), and we have previously shown that activated T cells lose the membrane expression of CD7331
Adenosine is a potent regulator of inflammation generated in the extracellular space by the sequential hydrolysis of ATP by ectonucleotidases CD39 and CD73

Summary

Introduction

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. 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. Our data reveal that CD73 contained in extracellular vesicles (EVs) derived from activated CD8 T cells is sufficient to degrade AMP and dampen T cell proliferation and function. This T cellintrinsic mechanism, in concerted action with a high ATPase activity of Tregs, mediates the production of adenosine from ATP, and warrants sufficient immune suppression. We find that EVs isolated from the synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA) induce T cell suppression in a CD73-dependent manner, underscoring the relevance of CD73 on EVs in the control of inflammation

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Results

Conclusion