CD73 ⁺ regulatory T cells contribute to adenosine‐mediated resolution of acute lung injury

Abstract

Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Since most cases of ALI resolve spontaneously, understanding the endogenous mechanisms that promote ALI resolution is important to developing effective therapies. Previous studies have implicated extracellular adenosine signaling in tissue adaptation and wound healing. Therefore, we hypothesized a functional contribution for the endogenous production of adenosine during ALI resolution. As a model, we administered intratracheal LPS and observed peak lung injury at 3 d, with resolution by d 14. Treatment with pegylated adenosine-deaminase to enhance extracellular adenosine breakdown revealed impaired ALI resolution. Similarly, genetic deletion of cd73, the pacemaker for extracellular adenosine generation, was associated with increased mortality (0% wild-type and 40% in cd73(-/-) mice; P<0.05) and failure to resolve ALI adequately. Studies of inflammatory cell trafficking into the lungs during ALI resolution revealed that regulatory T cells (Tregs) express the highest levels of CD73. While Treg numbers in cd73(-/-) mice were similar to controls, cd73-deficient Tregs had attenuated immunosuppressive functions. Moreover, adoptive transfer of cd73-deficient Tregs into Rag(-/-) mice emulated the observed phenotype in cd73(-/-) mice, while transfer of wild-type Tregs was associated with normal ALI resolution. Together, these studies implicate CD73-dependent adenosine generation in Tregs in promoting ALI resolution.

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…For example, a recent study demonstrated that Cd73 2/2 mice experience a dramatic failure to resolve lipopolysaccharide-induced inflammation due to a lack of regulatory T cells. 65 Similarly, Adora2b signaling has been implicated in promoting regulatory T cells and inflammation resolution. 66 Because T cell activation plays an important role in the pathophysiology of diabetic organ injury, 67 future studies toward a possible role of adenosine in regulating T-cell activation could be of great clinical relevance.…”

‘Repair’ Treg Cells in Tissue Injury

“…CCR7 deficiency contributed to Treg homeostasis and trafficking within the lungs, which further modulated wound repair in pulmonary fibrosis [31]. CD73-dependent adenosine generation in Tregs also promoted acute lung injury resolution [32]. Tregs limited injury by decreasing allergic airway inflammation and epithelial barrier disruption in house dust mite-derived protease induced-allergic disorders [33].…”

“…In mouse models with CD73 deficiency on T cells, enhanced tissue fibrosis and worse myocardial function were observed after MI, which was associated with accelerated production of pro-inflammatory and profibrotic cytokines (IL-2, INF-γ, IL-17) [75]. Similarly, genetic deletion of CD73 increased mortality and failure to resolve acute lung injury; however, transfer of wild type Tregs was associated with acute lung injury resolution in Rag-/- mice, which was not observed in mice with adoptive transfer of CD73-deficient Tregs [32]. Thus, evidence suggests that CD39/ CD73 is emerging as an important factor to control Treg-mediated repair, particularly in myocardial infarction.…”

Adenosine production: a common path for mesenchymal stem-cell and regulatory T-cell-mediated immunosuppression

“…Specifically for Tregs, adenosine role is underscored by several models of CD39 [183,184] and CD73 knockdown/Ko/blockade [185,186], which compromise Treg function. Regarding the role of adenosine for MSC function, literature is still restricted.…”