CD73+ Dendritic Cells in Cascading Th17 Responses of Experimental Autoimmune Uveitis-Induced Mice.

Minhee K Ko,Henry J Kaplan,Deming Sun,Hui Shao

doi:10.3389/fimmu.2020.601272

Minhee K Ko, Henry J Kaplan + Show 2 more

Open Access

https://doi.org/10.3389/fimmu.2020.601272

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Abstract

Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73+ BMDCs play a critical role in cascading Th17 responses, and CD73+ BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73−/− mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73+ DCs is critically involved in augmented Th17 responses. We conclude that CD73+ DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses.

Highlights

Under pathologic conditions, a large amount of adenosine triphosphate (ATP) is released into the extracellular compartment by injured and dying cells [1,2,3,4]
Since levels of extracellular adenosine increase greatly during inflammation [31,32,33], and since our previous studies showed that adenosine has an opposite effect on Th1 and Th17 pathogenic responses in experimental autoimmune uveitis, we examined whether adenosine and adenosine metabolism of dendritic cells (DCs) contribute to a biased effect of adenosine on Th1 and Th17 responses: whether CD73-expressing DCs differ in supporting Th1 vs Th17 responses
Our results show that Bone marrow dendritic cells (BMDCs) cultured with granulocyte–macrophage colony-stimulating factor (GM-CSF) do not express detectable levels of CD73; a significant portion of the BMDCs become CD73+ after exposure to Toll-like receptor (TLR) ligand or gd T cells, suggesting that CD73 is not constantly expressed by BMDCs but is inducible

Summary

Introduction

A large amount of adenosine triphosphate (ATP) is released into the extracellular compartment by injured and dying cells [1,2,3,4]. The released ATP acts as an endogenous Toll-like receptor (TLR) ligand to enhance immune responses and inflammation [5,6,7,8,9]. A combination of the ectoenzymes CD39 and CD73 degrades ATP, adenosine diphosphate (ADP), and adenosine monophosphate (AMP) to adenosine, thereby quenching the ATP-driven proinflammatory processes [10]. The metabolic process of ATP conversion to adenosine has been viewed as an ‘immunological switch’ that shifts ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state [12,13,14].

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