CD39+ Regulatory T Cells Attenuate Lipopolysaccharide-Induced Acute Lung Injury via Autophagy and the ERK/FOS Pathway

Front Immunol. 2021 Jan 8:11:602605. doi: 10.3389/fimmu.2020.602605. eCollection 2020.

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by an uncontrollable cytokine storm, which is associated with high mortality due to lack of effective treatment. Regulatory T cells (Tregs) play an indispensable role in maintaining immune homeostasis and CD39 is considered as a functional cell marker of Tregs. In this study, we aimed to evaluate the effect of CD39+ Tregs on acute lung injury (ALI) and investigate the frequency of CD39+ Tregs in ARDS patients. We found that after lipopolysaccharide (LPS) treatment, CD39-/- mice exhibited more severe inflammation and wild type (WT) mice exhibited a decreased frequency of CD39+ Tregs in the peripheral blood. Furthermore, CD39+ Tregs had a protective effect on LPS-induced inflammation in vitro and the adoptive transfer of CD39+ Tregs had a therapeutic effect on ALI in vivo. We further sought to explore the mechanisms that affect CD39 expression on Tregs. LPS-induced inflammation in the lung impaired the immunosuppressive effect of Tregs via the autophagy-mediated downregulation of CD39. In addition, CD39 induced the expression of itself in Tregs via activating the ERK1/2-FOS pathway. Consistent with this finding, the frequency of CD39+ Tregs was also decreased in the peripheral blood of ARDS patients and was positively correlated with disease severity. Our results suggested that the adoptive transfer of CD39+ Tregs may provide a novel method for the clinical prevention and treatment of ARDS.

Keywords: CD39; ERK; FOS; acute lung injury; acute respiratory distress syndrome; adoptive transfer; autography; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Acute Lung Injury* / genetics
  • Acute Lung Injury* / immunology
  • Acute Lung Injury* / pathology
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology*
  • Apyrase / genetics
  • Apyrase / immunology*
  • Autophagy* / drug effects
  • Autophagy* / genetics
  • Autophagy* / immunology
  • Lipopolysaccharides / toxicity*
  • MAP Kinase Signaling System* / drug effects
  • MAP Kinase Signaling System* / genetics
  • MAP Kinase Signaling System* / immunology
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology

Substances

  • Antigens, CD
  • Fos protein, mouse
  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-fos
  • Apyrase
  • CD39 antigen