Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β

Eur J Immunol. 2011 Oct;41(10):2955-65. doi: 10.1002/eji.201141512. Epub 2011 Sep 6.

Abstract

Levels of anti-inflammatory extracellular adenosine are controlled by the sequential action of the ectonucleotidases CD39 and CD73, whose expression in CD4(+) T cells has been associated with natural regulatory T cells (nTregs). We here show that CD73 expression on activated murine CD4(+) T cells is induced by TGF-β independently of Foxp3 expression, operates at the transcriptional level and translates into gain of functional capacity to generate adenosine. In the presence of AMP, CD73 induced by TGF-β generates adenosine able to suppress proliferation of activated CD4(+) T cells in vitro. These effects are contextual and opposed by proinflammatory cytokines. CD73 is also upregulated by TGF-β in CD8(+) T cells, DCs and macrophages, so providing an amplification mechanism for adenosine generation in tissue microenvironments. Together, these findings expose a novel anti-inflammatory role for TGF-β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / biosynthesis
  • 5'-Nucleotidase / metabolism*
  • Adenosine / metabolism*
  • Adenosine Monophosphate / metabolism
  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / metabolism
  • Antigens, Surface
  • Apyrase / biosynthesis
  • Apyrase / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / chemistry
  • Cell Proliferation
  • Cytokines / immunology
  • Cytokines / metabolism
  • Dendritic Cells / chemistry
  • Forkhead Transcription Factors / biosynthesis
  • Inflammation Mediators*
  • Leukocytes / metabolism*
  • Lymphocyte Activation*
  • Macrophages / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*

Substances

  • Antigens, CD
  • Antigens, Surface
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Inflammation Mediators
  • Transforming Growth Factor beta
  • Adenosine Monophosphate
  • 5'-Nucleotidase
  • Apyrase
  • CD39 antigen
  • Adenosine