Extracellular adenosine regulates naive T cell development and peripheral maintenance

Cekic C., Sag D., Day Y., Linden J.

JOURNAL OF EXPERIMENTAL MEDICINE, vol.210, no.12, pp.2693-2706, 2013 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 210 Issue: 12
  • Publication Date: 2013
  • Doi Number: 10.1084/jem.20130249
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.2693-2706
  • Dokuz Eylül University Affiliated: Yes


Adenosine produced as a byproduct of metabolic activity is present in all tissues and produces dose-dependent suppression of TCR signaling. Naive T cell maintenance depends on inhibition of TCR signals by environmental sensors, which are yet to be fully defined. We produced mice with a floxed adenosine A(2A) receptor (A(2A)R) gene, Adora2a, and show that either global A(2A)R deletion or cre-mediated T cell deletion elicits a decline in the number of naive but not memory T cells. A(2A)R signaling maintains naive T cells in a quiescent state by inhibiting TCR-induced activation of the phosphatidylinositide 3-kinase (PI3K)-AKT pathway, thereby reducing IL-7R alpha down-regulation and naive T cell apoptosis. Patterns of IL-7R alpha expression on T cells in chimeric mice reconstituted with Adora2a(+/+) and Adora2a(-/-) bone marrow cells suggest that decreased IL-7R alpha in naive T cells is a cell-intrinsic consequence of Adora2a deletion. In addition, A(2A)R expression increases in early thymic T cell development and contributes to progression of double-negative thymic precursors to single-positive thymocytes with increased IL-7R alpha expression. Therefore, A(2A)R signaling regulates T cell development and maintenance to sustain normal numbers of naive T cells in the periphery.